N-(heteroaryl)-sulfonamide derivatives useful as s100-inhibitors

ABSTRACT

A compound of formula (I), or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising the compound. The compound is an inhibitor of interactions between SI 00A9 and interaction partners such as RAGE, TLR4 and EMMPRIN and as such is useful in the treatment of disorders such as cancer, autoimmune disorders, inflammatory disorders and neurodegenerative disorders.

This application is a continuation of U.S. application Ser. No.14/890,938 filed on Nov. 13, 2015, which is a national phase ofInternational Application No. PCT/EP2014/059829 filed May 14, 2014 andpublished in the English language, which claims priority to ApplicationNo. EP 13167680.1 filed May 14, 2013.

FIELD OF THE INVENTION

The present invention relates to sulfonamide derivatives, pharmaceuticalcompositions of these derivatives and their use as medicaments. Moreparticulary the invention relates to sulfonamide derivatives for use inthe treatment of cancer, autoimmune disorders, inflammatory disordersand neurodegenerative disorders.

BACKGROUND OF THE INVENTION

S100A9 belongs to the S100-family of calcium-binding proteins and hasbeen recognized as an attractive novel therapeutic target for thetreatment of e.g. autoimmunity, inflammatory disease, neurodegenerativedisease and cancer. Other S100 proteins have distinct roles in manydifferent biological processes and are connected to a number of diseasesincluding cancer, cardiomyopathies, atherosclerosis, Alzheimer's diseaseand inflammatory diseases. Twenty-one of the human genes, includingS100A9, are located at chromosomal region 1q21, which is frequentlyaltered in tumors (Marenholz et al., 2004). Interestingly, although theprimary sequence diverges between family members, the 3D-structures ofthe different proteins are very similar.

S100A9 is often co-expressed with S100A8, another member of the S100protein family, and they are highly expressed in myeloid cells, such asneutrophils and monocytes, but can also be induced in other cells ortissues (Srikrishna 2012). They form non-covalent homo- andheterocomplexes that can be specifically released in response tocellular activation (Foell et al., 2007, Ryckman et al., 2003). S100A9can functionally be described as a damage-associated molecular pattern(DAMP) molecule which is released in tissues and induces signaling byinteracting with receptors such as RAGE and TLR4 (Foell et al., 2007,below). As for many other DAMP molecules, S100A9 also has intracellularroles in addition to its extracellular functions, e.g. by binding to thecytoskeleton and influencing cytoskeletal rearrangements and therebycellular migration (Srikrishna 2012).

A pro-inflammatory role for S100A9 is supported by elevated S100A9 serumlevels in inflammatory diseases and by high concentrations of S100A9 atlocal sites of inflammation, for example in the synovial fluid ofrheumatoid arthritis patients (Foell & Roth, 2004) or osteoarthritispatients (van Lent 2012) where high levels correlate with jointdestruction. Also, preclinical studies with S100A9 knock-out mice showan involvement of S100A9 in many inflammatory processes includingsynovial activation and cartilage destruction during osteoarthritis (vanLent 2012). High levels of S100A9 have also been found in several formsof cancer and a high expression level has been shown to correlate withpoor tumor differentiation in some of these cancer forms (Arai et al.,2001). Elevated S100A9 levels in pathological conditions of chronicinflammation as well as in cancer argue for a possible role ininflammation-associated carcinogenesis.

A role for S100A9 in the coupling between the immune system and canceris also supported by studies showing that S100A8 and S100A9 are highlyexpressed in and important for the function of myeloid-derivedsuppressor cells (MDSCs) (Cheng et al., 2008, Sinha et al., 2008, Wanget al., 2013), a mixture of immature myeloid cells that suppress T- andNK-cell activation and promote angiogenesis and tumor growth. Byinterfering with S100A9-regulated accumulation of tumor infiltratingMDSCs, the balance between these processes may change in favor of ananti-angiogenic and less immune suppressive milieu with inhibited tumorprogression. Furthermore, there are data suggesting a role for S100A9 inrecruiting both inflammatory cells and tumor cells to metastatic sites(Hiratsuka et al., 2006, Acharyya et al. 2012, Hibino et al., 2013).Thus, blocking the function of S100A9 may provide a new approach toprevention of metastasis.

Although a number of possible biological functions of S100A9 have beenproposed, the exact role of S100A9 in inflammation, in cancer and inother diseases is still unknown. Members of the S100 protein family havebeen reported to interact with the pro-inflammatory molecule RAGE andstudies showed that S100A9 is the strongest RAGE binder within the S100family in the presence of physiological levels of Ca²⁺ and Zn²⁺ (Björket al. 2009). These studies further demonstrated that S100A9 interactswith toll-like receptor 4 (TLR4). As for the S100A9-RAGE interaction,the S100A9-TLR4 interaction appears to be strictly dependent on thepresence of physiological levels of both Ca²⁺ and Zn²⁺. Another receptorfor S100A9 that may be important in cancer is EMMPRIN (CD147), thisprotein is expressed on different cell types and the S100A9-EMMPRINinteraction has been shown to be involved in melanoma metastasis (Hibinoet al., 2013).

S100A8 and S100A9 proteins have predominantly been described ascytoplasmic proteins that are secreted from myeloid cells uponactivation. It is generally believed that the major biological functionsrelevant to inflammation require the release of the S100 proteins to theextracellular space. In this model, extracellular S100A9 would bind toe.g. the pro-inflammatory receptors RAGE and TLR4 and result in aninflammatory response. This is supported by studies showing that S100A9induces TNFα production in human monocytes via TLR4 (Riva et al. 2012,Cesaro et al. 2012). Also, S100A9 in complex with S100A8 has showngrowth promoting activity directly on tumors cells via RAGE signaling(Ghavami et al., 2008). S100A9 also exists in a membrane-associated formon monocytes (Bhardwaj et al., 1992). Membrane associated S100A9 opensup for the possibility of cell-cell or cell-ECM signaling involvingS100A9.

The collected data suggest that S100A9 have important roles ininflammation, cancer growth, cancer metastasis and in their connections.Novel compounds that inhibit the activity of S100A9 in these processes,and thereby disturb the tumor microenvironment, would be attractive intreatment of cancer of different types.

Besides cancer, inflammation and autoimmunity, S100A9 has strongconnections to neurodegenerative disease. S100A9 is upregulated in thebrain in Alzheimer's disease (AD) patients and in mouse disease models(Shepherd et al., 2006, Ha et al., 2010). Furthermore, knock-down ordeletion of S100A9 in mice models of AD inhibits cognition decline andplaque burden in the brain (Ha et al., 2010, Chang et al., 2012). A rolefor RAGE is also evident in AD where inhibition of RAGE reduces diseasein a mouse AD model (Deane et al., 2013). Inhibition of S100A9 and itsinteractions represents a new promising approach for therapeuticintervention in AD and other neurodegenerative diseases.

Sulfonamides are known in the prior art. Thus, e.g. in EP1661889 A1N-[5-bromo-3-hydroxypyridin-2-yl]-4-methylbenzenesulfonamide isdisclosed as a synthesis intermediate. The compoundsN-(1,2-dihydro-2-oxo-3-pyridinyl)-2-(trifluoromethyl)-benzenesulfonamideand4-chloro-N-(1,2-dihydro-2-oxo-3-pyridinyl)-3-(trifluoromethyl)-benzenesulfonamideare disclosed in a chemical database (Database Chemcats XP002698561) andEnamine Advanced HTS Collection. In Hsieh Jui-Hua et al, J Comp-Aid MolDes, 22(9), 593, 2008,4-chloro-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide is described. InAndersen K et al, J Org Chem, 53(20), 4667, 1988,3-trifluoromethyl-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide isdescribed. In Andersen K et al, J Org Chem, 47(10), 1884, 1982,4-methyl-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide is described. InKoshiro A, Chem Pharm Bull, 7, 725, 1959,4-methyl-N-(2-hydroxy-3-pyridinyl)-benzenesulfonamide is described. InNakagone T et al, Chem Pharm Bull, 14(10), 1074, 1966,4-methyl-N-(2,3-dihydro-3-oxo-4-pyridazinyl)-benzenesulfonamide and itstautomer 4-methyl-N-(3-hydroxy-4-pyridazinyl)-benzenesulfonamide aredescribed.

SUMMARY OF THE INVENTION

In a first aspect, novel sulfonamide compounds are provided, accordingto formula (I)

or a pharmaceutically acceptable salt thereof;

wherein

-   -   W is N or CH;    -   X is N or CR₁;    -   Y is N or CR₂;    -   Z is N or CR₃;    -   at least one and at most two of W, X, Y and Z are N;    -   R₁ is H, halogen, S(O)₂C1-C3 alkyl, cyano, or C1-C3 alkyl        optionally substituted with one or more halogen(s);    -   R₂ is H, halogen, cyano, C(O)OH, C(O)OC1-C3 alkyl, C1-C3 alkyl        optionally substituted with one or more F; hydroxy-C1-C3 alkyl,        S(O)₂C1-C3 alkyl, S(O)₂C3-C6 cycloalkyl or S(O)₂C1-C3        hydroxyalkyl;    -   R₃ is H, halogen or cyano;    -   V is (CHR₄)_(m);    -   m is 0 or 1;    -   R₄ is H or C1-C3 alkyl optionally substituted with one or more        halogen(s);    -   Ar is

-   -   R₅ is H, halogen or cyano;    -   R₆ is H or halogen;    -   R₇ is H, halogen, C1-C3 alkyl, cyano, S(O)₂C1-C3 alkyl, or        phenyl;    -   R₈ is H, halogen, C1-C3 alkyl optionally substituted with one or        more F; C1-C3 alkoxy optionally substituted with one or more F;        phenoxy, NHR₁₁, or NR₁₁R₁₂;    -   R₉ is H, halogen, cyano, C1-C3 alkyl optionally substituted with        one or more F; C1-C3 alkylthio optionally substituted with one        or more F; C1-C3 alkoxy optionally substituted with one or more        F; or C(O)NR₁₃R₁₄;    -   R₁₀ is H, halogen, cyano, C1-C3 alkyl optionally substituted        with one or more F; C1-C3 alkylthio optionally substituted with        one or more F; C1-C3 alkoxy optionally substituted with one or        more F; or C(O)NR₁₃R₁₄;    -   R₁₁ is C1-C3 alkyl;    -   R₁₂ is C1-C3 alkyl; or    -   R₁₁ and R₁₂, together with the nitrogen atom to which they are        both attached, form a ring of formula

-   -   R₁₃ is H or C1-C3 alkyl; and    -   R₁₄ is H or C1-C3 alkyl;

provided that the compound is not selected from

-   3,4-difluoro-N-(2-hydroxypyridin-3-yl)benzene-1-sulfonamide,-   N-[5-bromo-3-hydroxypyridin-2-yl]-4-methylbenzenesulfonamide,-   N-(1,2-dihydro-2-oxo-3-pyridinyl)-2-(trifluoromethyl)-benzenesulfonamide,-   4-chloro-N-(1,2-dihydro-2-oxo-3-pyridinyl)-3-(trifluoromethyl)-benzenesulfonamide,-   4-chloro-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide,-   3-trifluoromethyl-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide,-   4-methyl-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide,-   4-methyl-N-(2-hydroxy-3-pyridinyl)-benzenesulfonamide, and-   4-methyl-N-(2,3-dihydro-3-oxo-4-pyridazinyl)-benzenesulfonamide or    its tautomer-   4-methyl-N-(3-hydroxy-4-pyridazinyl)-benzenesulfonamide.

The compounds of formula (I) as defined herein above are useful asinhibitors of interactions between S100A9 and interaction partners suchas RAGE, TLR4 and EMMPRIN. Thus, according to a further aspect,compounds of formula (I) as defined herein above are provided for use asinhibitors of interactions of S100A9 and its interaction partners andfor use in the treatment of disorders associated with functions ofS100A9, e.g. inflammatory diseases, neurodegenerative diseases,autoimmune diseases and cancer.

According to one aspect, compounds of formula (I) are provided for usein therapy, e.g. for the treatment of of a disorder selected frominflammatory diseases, neurodegenerative diseases, autoimmune diseasesand cancer.

According to one aspect, the use of compounds of formula (I) in themanufacturing of a medicament for use in the treatment of a disorderselected from inflammatory diseases, neurodegenerative diseases,autoimmune diseases and cancer.

According to a further aspect, a pharmaceutical composition is provided,comprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable excipient.The pharmaceutical composition of the invention is useful for thetreatment of diseases selected from inflammatory diseases, autoimmunediseases, neurodegenerative diseases and cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of an assay of the inhibition ofthe interaction between biotinylated human S100A9 and human RAGE-Fcusing a small molecule S100A9 binder.

FIGS. 2A, 2B and 2C are graphs showing the competitive binding of thecompound of Example 59 (ABR-238901) to S100A9 in the presence of (FIG.2A) RAGE, (FIG. 2B) TLR4/MD2 and (FIG. 2C) EMMPRIN. In the assay, S100A9was injected (2 min; 30 μL/min) at ˜1.3 μg/mL over amine coupled humanRAGE/Fc (density˜3.0 kRU), TLR4/MD2 (density˜3.9 kRU) or EMMPRIN/Fc(density˜2.9 kRU)+0.049-100 μM ABR-238901. Binding of S100A9 to (A)RAGE, (B) TLR4/MD2 or (C) EMMPRIN in the absence or presence ofcompetitor is expressed as responses in resonance units (RU) on theY-axis and were plotted versus competitor concentration and fit to asigmoidal dose-response model for calculation of concentration yielding50% inhibition (IC₅₀). Assay buffer—10 mM HEPES, 0.15 M NaCl, pH 7.4(HBS buffer), containing 0.005% v/v Surfactant P20, 1 mM Ca²⁺ and 20 μMZn²⁺. After each cycle, regeneration was made by a 30 μL pulse of 3 mMEDTA in HBS buffer.

FIGS. 3A and 3B are bar charts showing the effect of compound treatmenton MC38-C215 tumor growth. Mice were inoculated with tumor cells s.c.and treatment with (A) Example 63 (ABR-238581) as shown in FIG. 3A or(B) Example 59 (ABR-238901) as shown in FIG. 3B was started thefollowing day. Treatment (30 mg/kg) was given daily per orally. Atend-point (day 15 and 16, respectively), mice were sacrificed and tumorsexcised and weighed. Error bars indicate SEM. The difference in tumorweight between treatment groups was statistically evaluated bynon-parametric Mann-Whitney U test.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of the present invention, the term alkyl, either aloneor as part of a radical, includes straight or branched chain alkyl ofthe general formula C_(n)H_(2n+1).

The term C1-C3 alkyl includes methyl, ethyl, n-propyl and isopropyl.

The term phenyl refers to a C₆H₅ radical of the formula

For the purpose of the present invention, the term halogen refers to F,Cl, Br and I.

The term hydroxy refers to a radical of the formula —OH.

The term hydroxy-C1-C3 alkyl refers to an alkyl radical substituted witha hydroxy, e.g. 1-hydroxypropan-2-yl.

The term C1-C3 alkylthio refers to a radical of the formula —SR, whereinR is C1-C3 alkyl.

The term C1-C3 alkoxy refers to a radical of the formula —OR, wherein Ris C1-C3 alkyl.

The term phenoxy refers to a radical of the formula —OR wherein R isphenyl.

The term cyano refers to a radical of formula —C≡N (i.e. —CN).

The term S(O)₂C1-C3 alkyl refers to a radical of formula

wherein R is C1-C3 alkyl.

The term S(O)₂C3-C6 cycloalkyl refers to a radical of formula

wherein R is C3-C6 cycloalkyl.

The term S(O)₂C1-C3 hydroxyalkyl refers to a radical of formula

wherein R is C1-C3 hydroxyalkyl.

The term C(O)OC1-C3 alkyl refers to a radical of formula

wherein R is C1-C3 alkyl.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

The term pharmaceutically acceptable salt of a compound refers to a saltthat is pharmaceutically acceptable, as defined herein, and thatpossesses the desired pharmacological activity of the parent compound.Pharmaceutically acceptable salts include acid addition salts formedwith inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid; or formed with organic acids, e.g.acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid,citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid,gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, muconic acid,2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinicacid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid; orsalts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic or inorganicbase. Acceptable organic bases include e.g. diethanolamine,ethanolamine, N-methylglucamine, triethanolamine, morpholine, andtromethamine. Acceptable inorganic bases include e.g. ammonia, aluminumhydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate andsodium hydroxide.

Whenever a chiral carbon is present in a chemical structure, it isintended that all stereoisomers associated with that chiral carbon areencompassed by the structure, unless otherwise specified. Using theCahn-Ingold-Prelog RS notational system, any asymmetric carbon atom maybe present in the (R)- or (S)-configuration, and the compound may bepresent as a mixture of its stereoisomers, e.g. a racemic mixture, orone stereoisomer only.

Some of the compounds of the invention may exist in tautomeric forms,e.g. 2-hydroxypyridine and its tautomer 2-pyridone. Any such tautomer iscontemplated to be within the scope of the invention.

Also, in a compound of formula (I) as defined herein, any hydrogen atommay be replaced by a deuterium (²H), and any such deuterated compound offormula (I), comprising one or more deuteriums in place of thecorresponding number of hydrogen atoms, is considered to be within thescope of the invention.

The compounds of formula (I) carry a hydroxy group on the ringcontaining W, X, Y and Z. It has been found that the correspondingalkoxy compounds, i.e. where said hydroxyl group is alkylated, areprodrugs of the compounds of formula (I).

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,the disease state being treated, the severity of the disease treated,the age and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, etc.

As used herein the terms “treatment” or “treating” is an approach forobtaining beneficial or desired results including clinical results.Beneficial or desired clinical results can include, but are not limitedto, allevation or amelioration of one or more symptoms or conditions,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, preventing spread of disease, delay or slowing ofdisease progression, amelioration or palliation of the disease state,and remission (whether partial or total) whether detectable orundetectable. The term can also mean prolonging survival as compared toexpected survival without the treatment.

The term mammal refers to a human or any mammalian animal, e.g. aprimate, a farm animal, a pet animal, or a laboratory animal. Examplesof such animals are monkeys, cows, sheep, horses, pigs, dogs, cats,rabbits, mice, rats etc. Preferably, the mammal is a human.

The term cancer refers to any malignant growth or tumor caused byabnormal and uncontrolled cell division; it may spread to other parts ofthe body through the lymphatic system or the blood stream and includesboth solid tumors and blood-borne tumors. Exemplary cancers includeadrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma,anal cancer, anorectal cancer, appendix cancer, childhood cerebellarastrocytoma, childhood cerebral astrocytoma, basal cell carcinoma,biliary cancer, extrahepatic bile duct cancer, intrahepatic bile ductcancer, urinary bladder cancer, bone and joint cancer, osteosarcoma andmalignant fibrous histiocytoma, brain tumor, brain stem glioma,cerebellar astrocytoma, cerebral astrocytoma/malignant glioma,ependymoma, medulloblastoma, visual pathway and hypothalamic glioma,breast cancer, bronchial adenomas/carcinoids, nervous system cancer,nervous system lymphoma, central nervous system cancer, central nervoussystem lymphoma, cervical cancer, childhood cancers, chronic lymphocyticleukemia, chronic myelogenous leukemia, chronic myeloproliferativedisorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma,lymphoid neoplasm, mycosis fungoides, Sezary syndrome, endometrialcancer, esophageal cancer, extracranial germ cell tumor, extragonadalgerm cell tumor, eye cancer, retinoblastoma, gallbladder cancer, gastric(stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor (GIST), germ cell tumor, ovarian germ cell tumor,gestational trophoblastic tumor glioma, head and neck cancer,hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngealcancer, ocular cancer, Kaposi's sarcoma, renal cancer, laryngeal cancer,acute lymphoblastic leukemia, acute myeloid leukemia, hairy cellleukemia, lip and oral cavity cancer, lung cancer, non-small cell lungcancer, small cell lung cancer, non-Hodgkin's lymphoma, primary centralnervous system lymphoma, Waldenstrom's macroglobulinemia, intraocular(eye) melanoma, Merkel cell carcinoma, malignant mesothelioma,metastatic squamous neck cancer, cancer of the tongue, multipleendocrine neoplasia syndrome, myelodysplastic syndromes,myelodysplastic/myeloproliferative diseases, nasopharyngeal cancer,neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer,ovarian cancer, ovarian epithelial cancer, ovarian low malignantpotential tumor, pancreatic cancer, islet cell pancreatic cancer,paranasal sinus and nasal cavity cancer, parathyroid cancer, penilecancer, pheochromocytoma, pineoblastoma and supratentorial primitiveneuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiplemyeloma, pleuropulmonary blastoma, prostate cancer, rhabdomyosarcoma,salivary gland cancer, Ewing's sarcoma family of tumors, soft tissuesarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma),skin cancer (melanoma), small intestine cancer, squamous cell carcinoma,testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma,thyroid cancer, transitional cell cancer of the renal pelvis and ureterand other urinary organs, gestational trophoblastic tumor, urethralcancer, vaginal cancer, vulvar cancer, and Wilm's tumor.

The term autoimmune disorder (or autoimmune disease) refers to anydisorder arising from an inappropriate immune response of the bodyagainst substances and tissues normally present in the body(autoimmunity). Such response may be restricted to certain organs orinvolve a particular tissue in different places. Exemplary autoimmunedisorders are acute disseminated encephalomyelitis (ADEM), Addison'sdisease, agammaglobulinemia, alopecia areata, amyotrophic lateralsclerosis, ankylosing spondylitis, antiphospholipid syndrome,antisynthetase syndrome, atopic allergy, atopic dermatitis, autoimmuneaplastic anemia, autoimmune cardiomyopathy, autoimmune enteropathy,autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner eardisease, autoimmune lymphoproliferative syndrome, autoimmune peripheralneuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome,autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura,autoimmune urticarial, autoimmune uveitis, Balo disease/Balo concentricsclerosis, Behcet's disease, Berger's disease, Bickerstaffsencephalitis, Blau syndrome, bullous pemphigoid, Castleman's disease,celiac disease, Chagas disease, chronic inflammatory demyelinatingpolyneuropathy, chronic recurrent multifocal osteomyelitis, chronicobstructive pulmonary disease, Churg-Strauss syndrome, cicatricialpemphigoid, Cogan syndrome, cold agglutinin disease, complementcomponent 2 deficiency, contact dermatitis, cranial arteritis, CRESTsyndrome, Crohn's disease (one of two types of idiopathic inflammatorybowel disease “IBD”), Cushing's Syndrome, cutaneous leukocytoclasticangiitis, Dego's disease, Dercum's disease, dermatitis herpetiformis,dermatomyositis, diabetes mellitus type 1, diffuse cutaneous systemicsclerosis, Dressler's syndrome, drug-induced lupus, discoid lupuserythematosus, eczema, endometriosis, enthesitis-related arthritis,eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysisbullosa acquisita, erythema nodosum, erythroblastosis fetalis, essentialmixed cryoglobulinemia, Evan's syndrome, fibrodysplasia ossificansprogressive, fibrosing alveolitis (or Idiopathic pulmonary fibrosis),gastritis, gastrointestinal pemphigoid, glomerulonephritis,Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS),Hashimoto's encephalopathy, Hashimoto's thyroiditis, Henoch-Schonleinpurpura, herpes gestationis (aka gestational pemphigoid), Hidradenitissuppurativa, Hughes-Stovin syndrome, hypogammaglobulinemia, idiopathicinflammatory demyelinating diseases, idiopathic pulmonary fibrosis,idiopathic thrombocytopenic purpura, IgA nephropathy, inclusion bodymyositis, chronic inflammatory demyelinating polyneuropathy,interstitial cystitis, juvenile idiopathic arthritis (aka juvenilerheumatoid arthritis), Kawasaki's disease, Lambert-Eaton myasthenicsyndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus,linear IgA disease (LAD), lupoid hepatitis (aka autoimmune hepatitis),lupus erythematosus, Majeed syndrome, Meniere's disease, microscopicpolyangiitis, mixed connective tissue disease, morphea, Mucha-Habermanndisease (aka pityriasis lichenoides et varioliformis acuta), multiplesclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica(also Devic's disease), neuromyotonia, occular cicatricial pemphigoid,opsoclonus myoclonus syndrome, Ord's thyroiditis, palindromicrheumatism, PANDAS (pediatric autoimmune neuropsychiatric disordersassociated with streptococcus), paraneoplastic cerebellar degeneration,paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome,Parsonage-Turner syndrome, pars planitis, pemphigus vulgaris, perniciousanaemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritisnodosa, polymyalgia rheumatic, polymyositis, primary biliary cirrhosis,primary sclerosing cholangitis, progressive inflammatory neuropathy,psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cellaplasia, Rasmussen's encephalitis, Raynaud phenomenon, relapsingpolychondritis, Reiter's syndrome, restless leg syndrome,retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever,sarcoidosis, schizophrenia, Schmidt syndrome another form of APS,Schnitzler syndrome, Scleritis, Scleroderma, Serum Sickness, Sjögren'ssyndrome, spondyloarthropathy, stiff person syndrome, subacute bacterialendocarditis (SBE), Susac's syndrome, Sweet's syndrome, sympatheticophthalmia, systemic lupus erythematosis, Takayasu's arteritis, temporalarteritis (also known as “giant cell arteritis”), thrombocytopenia,Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis (one oftwo types of idiopathic inflammatory bowel disease “IBD”),undifferentiated connective tissue disease different from mixedconnective tissue disease, undifferentiated spondyloarthropathy,urticarial vasculitis, vasculitis, vitiligo, and Wegener'sgranulomatosis.

The term inflammatory disorder (or inflammatory disease) refers to apathological state associated with inflammation, typically caused byleukocyte infiltration. The inflammatory disorder may be acute orchronic. Exemplary inflammatory disorders include inflammatory skindiseases, including, without limitation, psoriasis and atopicdermatitis, systemic scleroderma and sclerosis, responses associatedwith inflammatory bowel disease (IBD) (such as Crohn's disease andulcerative colitis), ischemic reperfusion disorders including surgicaltissue reperfusion injury, myocardial ischemic conditions such asmyocardial infarction, cardiac arrest, reperfusion after cardiac surgeryand constriction after percutaneous transluminal coronary angioplasty,stroke, and abdominal aortic aneurysms, cerebral edema secondary tostroke, cranial trauma, hypovolemic shock, asphyxia, adult respiratorydistress syndrome, acute-lung injury, Behcet's Disease, dermatomyositis;polymyositis; multiple sclerosis (MS); dermatitis; meningitis;encephalitis; uveitis, osteoarthritis, lupus nephritis, autoimmunediseases such as rheumatoid arthritis (RA), Sjörgen's syndrome,vasculitis, diseases involving leukocyte diapedesis, central nervoussystem (CNS) inflammatory disorder, multiple organ injury syndromesecondary to septicemia or trauma, alcoholic hepatitis, bacterialpneumonia, antigen-antibody complex mediated diseases includingglomerulonephritis, sepsis, sarcoidosis, immunopathologic responses totissue or organ transplantation, inflammations of the lung, includingpleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis,bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis,idiopathic pulmonary fibrosis (IPF), and cystic fibrosis, etc.

The term neurogenerative disorder (or neurogenerative disease) refers todisorders associated with a progressive loss of structure or function ofneurons affecting the structure or function of the brain, spinal cord orperipheral nervous system. Exemplary neurodegenerative disorders includemitochondrial encephalomyopathies and gut dysmotility syndromes, ataxiasyndromes including Friedreich's ataxia and spinocerebellar ataxia(SCA), spinal cord injury, familial and sporadic amyotrophic lateralsclerosis (FALS and ALS, respectively), familial and sporadicParkinson's disease, familial and sporadic Alzheimer's disease,Huntington's disease, olivopontocerebellar atrophy, multiple systematrophy, progressive supranuclear palsy, diffuse lewy body disease andsynucleinopathies, Down Syndrome, corticodentatonigral degeneration,progressive familial myoclonic epilepsy, strionigral degeneration,torsion dystonia, familial tremor, Gilles de la Tourette syndrome, andHallervorden-Spatz disease.

The term excipient refers to pharmaceutically acceptable chemicals, suchas known to those of ordinary skill in the art of pharmacy to aid theadministration of the medicinal agent. It a compound that is useful inpreparing a pharmaceutical composition, generally safe, non-toxic andneither biologically nor otherwise undesirable, and includes excipientsthat are acceptable for veterinary use as well as human pharmaceuticaluse.

Exemplary excipients include binders, surfactants, diluents,disintegrants, antiadherents, and lubricants.

According to a first aspect, a compound of formula (I)

is provided, as defined herein above.

In some embodiments, in a compound of formula (I),

-   -   W is N or CH;    -   X is N or CR₁;    -   Y is N or CR₂;    -   Z is N or CR₃;    -   at least one and at most two of W, X, Y and Z are N;    -   R₁ is H or halogen;    -   R₂ is H, halogen, cyano, C(O)OH, C(O)OC1-C3 alkyl, C1-C3 alkyl,        hydroxy-C1-C3 alkyl, or S(O)₂C1-C3 alkyl;    -   R₃ is H or halogen;    -   V is (CHR₄)_(m);    -   m is 0 or 1;    -   R₄ is H or methyl;    -   Ar is

-   -   R₅ is H or halogen;    -   R₆ is H or halogen;    -   R₇ is H, halogen, C1-C3 alkyl, or phenyl;    -   R₈ is H, halogen, C1-C3 alkyl optionally substituted with one or        more F; C1-C3 alkoxy optionally substituted with one or more F,        phenoxy, NHR₁₁, or NR₁₁R₁₂;    -   R₉ is H, halogen, cyano, C1-C3 alkyl optionally substituted with        one or more F, C1-C3 alkoxy optionally substituted with one or        more F, or C(O)NR₁₃R₁₄;    -   R₁₀ is H, halogen, cyano, C1-C3 alkyl optionally substituted        with one or more F, C1-C3 alkoxy optionally substituted with one        or more F, or C(O)NR₁₃R₁₄;    -   R₁₁ is C1-C3 alkyl;    -   R₁₂ is C1-C3 alkyl; or    -   R₁₁ and R₁₂, together with the nitrogen atom to which they are        both attached, form a ring of formula

-   -   R₁₃ is H or C1-C3 alkyl; and    -   R₁₄ is H or C1-C3 alkyl.

In a compound of formula (I), W is N or CH; X is N or CR₁; Y is N orCR₂; and Z is N or CR₃; and at least one and at most two of W, X, Y andZ are N.

In a compound formula (I), R₁ is H, halogen, e.g. Cl or Br; S(O)₂C1-C3alkyl, e.g. CH₃S(O)₂; cyano, or C1-C3 alkyl, e.g. methyl, optionallysubstituted with one or more F, such as CF₃; R₂ is H, halogen, cyano,C(O)OH, C(O)OC1-C3 alkyl, C1-C3 alkyl optionally substituted with one ormore F, hydroxy-C1-C3 alkyl, S(O)₂C1-C3 alkyl, S(O)₂C3-C6 cycloalkyl orS(O)₂C1-C3 hydroxyalkyl; and R₃ is H, halogen or cyano.

In some embodiments, R₁ is H or halogen, e.g. H or Cl; R₂ is H, halogen,e.g. Cl or Br; cyano; C(O)OH; C(O)OC1-C3 alkyl, e.g. C(O)OCH₃; C1-C3alkyl, e.g. CH(CH₃)₂; hydroxy-C1-C3 alkyl, e.g. CH(CH₃)CH₂OH; orS(O)₂C1-C3 alkyl, e.g. SO₂CH₃; and R₃ is H or halogen, e.g. H, Cl or Br,e.g. Cl or Br.

In some embodiments, the moiety R₁ is H, halogen, e.g. Cl or Br, e.g.Cl; S(O)₂C1-C3 alkyl, e.g. CH₃S(O)₂; cyano, or C1-C3 alkyl, e.g. methyl,optionally substituted with one or more F, e.g. CF₃.

In some embodiments, R₁ is H or halogen, e.g. H, Cl, or Br, inparticular H or Cl. In some embodiments, R₁ is halogen, e.g. R₁ is Cl orBr, in particular Cl. In some other embodiments, R₁ is H.

In some embodiments, R₁ is selected from H, Cl, Br, CH₃S(O)₂, cyano andCF₃.

The moiety R₂ is H, halogen, cyano, C(O)OH, C(O)OC1-C3 alkyl, C1-C3alkyl optionally substituted with one or more F, hydroxy-C1-C3 alkyl,S(O)₂C1-C3 alkyl, S(O)₂C3-C6 cycloalkyl or S(O)₂C1-C3 hydroxyalkyl.

When R₂ is halogen, it e.g. may be Cl, Br or I, in particular Cl or Br,more particularly Cl.

When R₂ is C(O)OC1-C3 alkyl, it e.g. may be C(O)OC1-C2 alkyl, e.g.C(O)OCH₃.

When R₂ is C1-C3 alkyl optionally substituted with one or more F, ite.g. may be CF₃.

When R₂ is hydroxy-C1-C3 alkyl, it e.g. may be CH(CH₃)CH₂OH.

When R₂ is S(O)₂C1-C3 alkyl, it e.g. may be CH₃S(O)₂, CH₃CH₂S(O)₂,(CH₃)₂CHS(O)₂ or CH₃CH₂CH₂SO₂.

When R₂ is S(O)₂C3-C6 cycloalkyl, it e.g. may be S(O)₂C4-C6 cycloalkyl,or S(O)₂C4-C5 cycloalkyl, e.g. cyclopentanesulfonyl.

When R₂ is S(O)₂C1-C3 hydroxyalkyl, it e.g. may be OHCH₂CH₂CH₂S(O)₂(3-hydroxypropanesulfonyl).

In some embodiments, R₂ is H, halogen, C(O)OH, C(O)OC1-C3 alkyl, C1-C3alkyl optionally substituted with one or more F, hydroxy-C1-C3 alkyl,S(O)₂C1-C3 alkyl, S(O)₂C3-C6 cycloalkyl or S(O)₂C1-C3 hydroxyalkyl.

In some embodiments, R₂ is H, halogen, C(O)OH, C(O)OC1-C3 alkyl, C1-C3alkyl optionally substituted with one or more F, S(O)₂C1-C3 alkyl,S(O)₂C3-C6 cycloalkyl or S(O)₂C1-C3 hydroxyalkyl.

In some embodiments, R₂ is H, halogen, C(O)OC1-C3 alkyl, C1-C3 alkyloptionally substituted with one or more F, S(O)₂C1-C3 alkyl, S(O)₂C3-C6cycloalkyl or S(O)₂C1-C3 hydroxyalkyl.

In some embodiments, R₂ is H, Cl, Br, I, cyano, C(O)OH, C(O)OCH₃,CH(CH₃)₂, CF3, (CH₂OH)(CH₃)CH—), CH₃S(O)₂, CH₃CH₂S(O)₂, (CH₃)₂CHS(O)₂,CH₃CH₂CH₂S(O)₂, cyclopentanesulfonyl, or CH₂(OH)CH₂CH₂S(O)₂.

In some embodiments, R₂ is H, halogen, cyano, C(O)OH, C(O)OC1-C3 alkyl,C1-C3 alkyl, hydroxy-C1-C3 alkyl, or S(O)₂C1-C3 alkyl. For example, R₂may be selected from H, Cl, Br, cyano, COOH, COOCH₃, CH₃, CH₃CH₂,CH(CH₃)₂, CH(CH₃)CH₂OH, and SO₂CH₃.

In some embodiments, R₂ is H, halogen, cyano, C(O)OH, C(O)OC1-C3 alkyl,C1-C3 alkyl, hydroxy-C1-C3 alkyl, or S(O)₂C1-C3 alkyl. For example, R₂may be selected from H, Cl, Br, cyano, COOH, COOCH₃, CH₃, CH₃CH₂,CH(CH₃)₂, CH(CH₃)CH₂OH, and SO₂CH₃.

In some embodiments, R₂ is selected from H, halogen, C(O)OC1-C3 alkyl,C1-C3 alkyl, hydroxy-C1-C3 alkyl, and S(O)₂C1-C3 alkyl. For example, R₂may be selected from H, Cl, Br, C(O)OCH₃, CH₃, CH₃CH₂, (CH₃)₂CH,CH(CH₃)CH₂OH, and SO₂CH₃.

In some embodiments, R₂ is H, halogen, cyano, C(O)OH, C(O)OC1-C3 alkyl,hydroxy-C1-C3 alkyl, or S(O)₂C1-C3 alkyl, e.g. H, halogen, hydroxy-C1-C3alkyl, or S(O)₂C1-C3 alkyl. For example, R₂ may be selected from H, Cl,Br, cyano, C(O)OH, COOCH₃, CH(CH₃)CH₂OH, and SO₂CH₃.

In some embodiments, R₂ is H, halogen, cyano, S(O)₂C1-C3 alkyl,S(O)₂C3-C6 cycloalkyl or S(O)₂C1-C3 hydroxyalkyl, e.g. R₂ is H, halogen,cyano or S(O)₂C1-C3 alkyl; e.g. H, halogen, or S(O)₂C1-C3 alkyl; orS(O)₂C1-C3 alkyl.

In some embodiments, R₂ is H, halogen, or S(O)₂C1-C3 alkyl, S(O)₂C3-C6cycloalkyl or S(O)₂C1-C3 hydroxyalkyl, e.g. R₂ is H, S(O)₂C1-C3 alkyl,S(O)₂C3-C6 cycloalkyl or S(O)₂C1-C3 hydroxyalkyl.

In some embodiments, R₂ is H, cyano, S(O)₂C1-C3 alkyl, S(O)₂C3-C6cycloalkyl or S(O)₂C1-C3 hydroxyalkyl, e.g. R₂ is H, cyano, orS(O)₂C1-C3 alkyl.

In some embodiments, R₂ is H or halogen or cyano, e.g. H or cyano.

In some embodiments, R₂ is H or halogen, e.g. R₂ is H, Cl or Br; or R₂is H or Cl.

In some embodiments, R₂ is as defined herein, but R₂ is not H.

The moiety R₃ is H, halogen or cyano. In some embodiments, R₃ is H orhalogen, e.g. H, Cl or Br, in particular H or Cl. In some embodiments,R₃ is H. In some other embodiments, R₃ is halogen, e.g. Cl or Br, inparticular Cl.

In some embodiments, R₁ is H, R₂ is as defined herein, and R₃ is H.

In some embodiments, R₁, R₂ and R₃ are as defined herein, but at leastone of R₁, R₂ and R₃ is not H. In some other embodiments, R₁, R₂ and R₃are as defined herein, but at least one of R₁, R₂ and R₃ is H. In someother embodiments, R₁, R₂ and R₃ are as defined herein, but at least twoof R₁, R₂ and R₃ are H. In some other embodiments, R₁, R₂ and R₃ are allH.

In some embodiments, W is N or CH; X is N or CH; Y is N or CR₂; and Z isN or CH; at least one and at most two of W, X, Y and Z are N; and R₂ isas defined herein.

In formula (I), at least one and at most two of W, X, Y and Z are N. Insome embodiments, W is N; X is N or CR₁; Y is N or CR₂; and Z is N orCR₃, and at most one of X, Y and Z is N, and the compound may then berepresented by formula (Ia)

wherein Ar, V, X, Y and Z are as defined herein.

In some particular embodiments, W is N, Y is CR₂, and Z is CH; and thecompound may then be represented by formula (Ia-1)

wherein Ar and V are as defined herein, X is N or CR₁, and R₂ is asdefined herein, e.g.

R₂ is halogen, cyano or S(O)₂C1-C3 alkyl, in particular R₂ is halogen orS(O)₂C1-C3 alkyl.

In some other embodiments, W is N or CH; X is N; Y is N or CR₂; and Z isN or CR₃, and at most one of W, Y and Z is N, and the compound may thenbe represented by formula (Ib)

wherein Ar, V, W, Y and Z are as defined herein.

In still other embodiments, W is N or CH; X is N or CR₁; Y is N; and Zis N or CR₃, and at most one of W, X and Z is N, and the compound maythen be represented by formula (Ic)

wherein Ar, V, W, X and Z are as defined herein.

In other embodiments, W is N or CH; X is N or CR₁; Y is N or CR₂; and Zis N, and at most one of W, X and Y is N, and the compound may then berepresented by formula (Id)

wherein Ar, V, W, X and Y are as defined herein.

In some particular embodiments, W is CH or N, X is CH, Y is CR₂, and Zis N, and the compound may then be represented by formula (Id-1)

wherein Ar, V, and R₂ are as defined herein, e.g R₂ is cyano, halogen orS(O)₂C1-C3 alkyl, e.g. R₂ is halogen or S(O)₂C1-C3 alkyl,

In some other particular embodiments, W is CH, X is CH, Y is CR₂, and Zis N, and the compound may then be represented by formula (Id-2)

wherein Ar, V, and R₂ are as defined herein, e.g R₂ is cyano, halogen orS(O)₂C1-C3 alkyl, e.g. R₂ is halogen or S(O)₂C1-C3 alkyl,

In some other particular embodiments, W is CH, X is CR₁, Y is CH, and Zis N, and the compound may then be represented by formula (Id-3)

wherein Ar, V, and R₁ are as defined herein, e.g R₁ is halogen.

In some embodiments, only one of W, X, Y and Z is N. For example, W isN; X is CR₁; Y is CR₂; and Z is CR₃, and the compound may then berepresented by formula (Ie)

wherein Ar, V, R₁, R₂ and R₃ are as defined herein.

In some particular embodiments, W is N; X is CH; Y is CR₂; and Z is CH,and the compound may then be represented by formula (Ie-1)

wherein Ar, V, R₁, R₂ and R₃ are as defined herein, e.g. R₂ isS(O)₂C1-C3 alkyl,

In some other embodiments, when only one of W, X, Y and Z is N, X is N,W is CH, Y is CR₂, and Z is CR₃, and the compound may then berepresented by formula (If)

wherein Ar, V, R₂ and R₃ are as defined herein.

In some particular embodiments, X is N, W and Y are both CH, and Z isCR₃, and the compound may then be represented by formula (If-1)

wherein Ar, V and R₃ are as defined herein, e.g. R₃ is halogen.

In some other particular embodiments, X is N, and W, Y and Z are all CH,and the compound may then be represented by formula (If-2)

wherein Ar and V are as defined herein.

In other embodiments, when only one of W, X, Y and Z is N, W is CH, X isCR₁, Y is CR₂ and Z is N.

In some embodiments according to formulas (Ia), (Ib), and (Id) Y is CR₂,wherein R₂ is as defined herein.

In some embodiments, in a compound of formula (Ia), X is CH, Y is CR₂,and Z is CH;

the compound may then be represented by formula (Ig)

wherein Ar, V, and R₂ are as defined herein.

In some embodiments, two of W, X, Y and Z are N, e.g. W and X or W and Zare N. In some embodiments, the two N are adjacent, e.g. W and X are N.In some other embodiments, the two N are non-adjacent e.g. W and Z areN, or Z and X are N.

Thus, in some embodiments, W and X are N, and the compound of theinvention may be represented by formula (Ih)

wherein Ar, V, R₂ and R₃ are as defined herein.

In some particular embodiments, W and X are N, Y is CR₂, and Z is CH,and the compound of the invention may be represented by formula (Ih-1)

wherein Ar, V, and R₂ are as defined herein, e.g. R₂ is halogen orS(O)₂C1-C3 alkyl.

In some other embodiments, W and Z are N, and the compound of theinvention may be represented by formula (Ij)

wherein Ar, V, R₁ and R₂ are as defined herein.

In some particular embodiments, W is N, X is CH, Y is CR₂ and Z is N,and the compound of the invention may be represented by formula (Ij-1)

wherein Ar, V, R₂ are as defined herein, e.g. R₂ is halogen, S(O)₂C1-C3alkyl or cyano.

In still other embodiments, W and Y are N, and the compound of theinvention may be represented by formula (Ik)

wherein Ar, V, R₁ and R₃ are as defined herein.

In still other embodiments, X and Z are N, and the compound of theinvention may be represented by formula (Im)

wherein Ar, V and R₂ are as defined herein.

In some particular embodiments, the moiety

is selected from:

In a compound of formula (I) as defined herein, V is (CHR₄)_(m), whereinm is 0 or 1, and R₄ is H or C1-C3 alkyl optionally substituted with oneor more F. In some embodiments, R₄ is H or methyl, optionallysubstituted with one or more F, e.g R₄ is H or CF₃, or R₄ is H.

In some embodiments, m is 0, i.e. the compound may be represented byformula (In)

wherein Ar, W, X, Y and Z are as defined herein.

In some other embodiments, m is 1, i.e. the compound may be representedby formula (Io)

wherein Ar, R₄, W, X, Y and Z are as defined herein.

The moiety R₄ is H or C1-C3 alkyl optionally substituted with one ormore F. In some embodiments R₄ is H or CH₃. In some embodiments, R₄ isH, and a compound of formula (Io) may then be represented by formula(Ip)

wherein Ar, W, X, Y and Z are as defined herein.

In formula (I), the moiety Ar is

In some embodiments, Ar is

and the compound of formula (I) may then be represented by formula (Iq)

wherein R₅, R₆, V, W, X, Y and Z are as defined herein.

In a compound of formula (Iq), R₅ is H, halogen or cyano, e.g. R₅ is Hor halogen, and R₆ is H or halogen. In some embodiments, R₅ is halogenor cyano and R₆ is H or halogen. In some embodiments, at least one of R₅and R₆ is halogen. In some embodiments, both R₅ and R₆ are halogen, e.g.both R₅ and R₆ are C1. In some embodiments, R₅ is cyano and R₆ is H orhalogen, in particular H.

In some embodiments, in a compound of formula (Iq), the moiety

is 2,5-dichlorothiophen-3-yl or 5-cyanothiophen-3-yl.

In some embodiments, Ar is

and the compound of formula (I) may then be represented by formula (Ir)

wherein R₇, R₈, V, W, X, Y and Z are as defined herein.

In a compound of formula (Ir), R₇ is H, halogen, C1-C3 alkyl, cyano,S(O)₂C1-C3 alkyl, or phenyl, e.g. H, halogen, C1-C3 alkyl or phenyl; andR₈ is H, halogen, C1-C3 alkyl optionally substituted with one or more F,C1-C3 alkoxy optionally substituted with one or more F, phenoxy, NHR₁₁,or NR₁₁R₁₂. For example, in some embodiments, R₇ is H, Cl, Br or CH₃SO₂;and R₈ is H, Cl, CH₃, CF₃, CH₃O, CH₃CH₂O, (CH₃)₂CHO, phenoxy,((CH₃)₂CH)NH, (CH₃)₂N, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl.

In some embodiments, R₇ is H, halogen, C1-C3 alkyl, cyano or S(O)₂C1-C3alkyl; e.g. H, halogen, C1-C3 alkyl, or S(O)₂C1-C3 alkyl; or H, halogen,or S(O)₂C1-C3 alkyl.

When R₇ is halogen, it e.g. is Cl or Br, in particular Br.

When R₇ is S(O)₂C1-C3 alkyl, it e.g. is CH₃S(O)₂.

For example, in some embodiments, R₇ is H, halogen, methyl, phenyl orS(O)₂C1-C3 alkyl; e.g. H, halogen or S(O)₂C1-C3 alkyl; in particular Hor halogen; and R₈ is H, halogen, methyl, ethyl, isopropyl,trifluoromethyl, methoxy, trifluoromethoxy, phenoxy, NHR₁₁, or NR₁₁R₁₂.

In some embodiments, R₇ is H or halogen, e.g. H, Cl or Br, in particularH or Br.

In some embodiments, R₇ is as defined herein, but R₇ is not H. In someother embodiments, R₇ is H.

The moiety R₈ is H, halogen, C1-C3 alkyl, optionally substituted withone or more F; C1-C3 alkoxy optionally substituted with one or more F;phenoxy, NHR₁₁, or NR₁₁R₁₂.

When R₈ is halogen, it e.g. may be Cl.

When R₅ is C1-C3 alkyl, optionally substituted with one or more F; ite.g. may be CH₃ or CF₃, in particular it may be CF₃.

When R₅ is C1-C3 alkoxy optionally substituted with one or more F; ite.g. may be CH₃O, CH₃CH₂O or (CH₃)₂CHO, in particular CH₃O.

When R₅ is NHR₁₁, it e.g. may be ((CH₃)₂CH)NH.

When R₈ is NR₁₁R₁₂, it e.g. may be (CH₃)₂N or

in particular

In some embodiments, R₈ is H, halogen, C1-C3 alkyl optionallysubstituted with one or more F; C1-C3 alkoxy optionally substituted withone or more F; NHR₁₁ or NR₁₁R₁₂; e.g. R₈ is H, Cl, methoxy,trifluoromethyl, NHR₁₁, or NR₁₁R₁₂.

For example, R₇ is H or Br; and R₈ is H, Cl, methoxy, trifluoromethyl,NH(CH(CH₃)₂) or pyrrolidin-1-yl.

In NR₁₁R₁₂, the moieties R₁₁ and R₁₂ are independently selected fromC1-C3 alkyl, e.g. both are methyl; or R₁₁ and R₁₂, together with thenitrogen atom to which they are both attached, form a ring of formula

i.e. a ring selected from

In some embodiments, when NR₁₁R₁₂ form a ring, the ring is 4- or5-membered, i.e. it is azetidin-1-yl or pyrrolidin-1-yl. In some otherembodiments, the when NR₁₁R₁₂ form a ring, the ring is 5- or 6-membered,i.e. it is pyrrolidin-1-yl or piperidin-1-yl, in particularpyrrolidin-1-yl.

In some embodiments, the moiety

is selected from:

In some embodiments of a compound of formula (I), Ar is

and the compound of formula (I) may then be represented by formula (Is)

wherein R₉, R₁₀, V, W, X, Y and Z are as defined herein.

In a compound of formula (Is), R₉ and R₁₀ are independently selectedfrom H, halogen, cyano, C1-C3 alkyl optionally substituted with one ormore F; C1-C3 alkylthio optionally substituted with one or more F; C1-C3alkoxy optionally substituted with one or more F; and C(O)NR₁₃R₁₄. Forexample, R₉ and R₁₀ may be independently selected from H, F, Cl, Br, CN,CH₃, C₃H₇ (e.g. CH₃CH₂CH₂), CF₃, CH₃CH₂S, CH₃O, CF₃O, C(O)NH₂, andC(O)N(CH₂CH₃)₂.

In some embodiments, R₉ and R₁₀ are independently selected from H, F,Cl, Br, CN, CF₃, CF₃O, and C(O)NH₂.

In some embodiments, R₉ and R₁₀ are independently selected from H,halogen, cyano, C1-C3 alkoxy optionally substituted with one or more F;and C(O)NR₁₃R₁₄.

In some embodiments, one of R₉ and R₁₀, is selected from H and halogen,e.g. from H, F, Cl and Br; or from H, F and Cl, e.g. H and Cl. In otherembodiments, both R₉ and R₁₀ are selected from H and halogen, e.g. fromH, F, Cl and Br; or from H, F and Cl, e.g. H and Cl. For example, bothR₉ and R₁₀ are halogen, e.g. F, Cl or Br, such as F or Cl, in particularCl.

In some embodiments, one of R₉ and R₁₀ is halogen and the other one isselected from H, halogen, cyano, C1-C3 alkyl optionally substituted withone or more F; C1-C3 alkylthio optionally substituted with one or moreF; C1-C3 alkoxy optionally substituted with one or more F; andC(O)NR₁₃R₁₄. For example, one of R₉ and R₁₀ is halogen and the other oneis a moiety as defined herein, i.e. selected from H, halogen, cyano,C1-C3 alkyl optionally substituted with one or more F; C1-C3 alkylthiooptionally substituted with one or more F; C1-C3 alkoxy optionallysubstituted with one or more F; and C(O)NR₁₃R₁₄; such as from F, Cl, Br,CN, CH₃, C₃H₇ (e.g. CH₃CH₂CH₂), CF₃, CH₃CH₂S, CH₃O, CF₃O, C(O)NH₂, andC(O)N(CH₂CH₃)₂.

In some other embodiments, one of R₉ and R₁₀ is halogen and the otherone is selected from H, halogen, cyano, C1-C3 alkyl optionallysubstituted with one or more F; C1-C3 alkoxy optionally substituted withone or more F; and C(O)NR₁₃R₁₄. For example, one of R₉ and R₁₀ ishalogen and the other one is a moiety as defined herein, i.e. selectedfrom H, halogen, cyano, C1-C3 alkyl optionally substituted with one ormore F; C1-C3 alkoxy optionally substituted with one or more F; andC(O)NR₁₃R₁₄; such as from F, Cl, Br, CN, CF₃, CF₃O, and C(O)NH₂.

In some embodiments, R₉ is as defined herein, but is different from H.For example, R₉ is different from H and is located in meta or paraposition.

In some embodiments, e.g. when at least R₉ is different from H, or bothR₉ and R₁₀ are different from H, R₉ and R₁₀ are located in meta andmeta′ position, i.e. the compound of formula (I) may be represented byformula (It)

wherein R₉, R₁₀, V, W, X, Y and Z are as defined herein.

In some other embodiments, e.g. when at least R₁₀ is different from H,or both R₉ and R₁₀ are different from H, R₉ and R₁₀ are located in metaand para position, i.e. the compound of formula (I) may be representedby formula (Iu)

wherein R₉, R₁₀, V, W, X, Y and Z are as defined herein.

In still other embodiments, e.g. when at least R₉ is different from H,or both R₉ and R₁₀ are different from H, R₉ is in ortho position, i.e.the compound of formula (I) may be represented by formula (Iv)

wherein R₉, R₁₀, V, W, X, Y and Z are as defined herein.

In the moiety C(O)NR₁₃R₁₄. R₁₃ and R₁₄ are independently selected from Hand C1-C3 alkyl, e.g. from H, methyl and ethyl, or from H and methyl. Insome embodiments, both R₁₃ and R₁₄ are H. In some other embodiments,both R₁₃ and R₁₄ are C1-C3 alkyl, e.g. methyl or ethyl. For example,both R₁₃ and R₁₄ may be ethyl.

In some embodiments the moiety

is selected from

From the above, it appears that the compound of formula (I) may varywith respect to features of essentially three main parts of the compoundof formula (I), i.e. the ring containing W, X, Y and Z, as e.g.represented by formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ij), (Ik) and (Im); the moiety V, as e.g. represented by formulas (In),(Io) and (Ip), and the moiety Ar, as e.g. represented by formulas (Iq),(Ir), (Is), (It), (Iu) and (Iv). It should be realized that anycombination of the various embodiments relating to these three mainparts is an embodiment within the scope of the invention and is coveredby formula (I).

For example, in some embodiments, the compound is as represented byformula (Ia), in particular formula (Ie), or formula (Ig), or formula(Ih), (Ij) or (Ik), m is 0, and Ar is as generally defined in formula(I).

In some other embodiments, the compound is as represented by formula(Ia), in particular formula (Ie), or formula (Ig), or formula (Ih), (Ij)or (Ik), m is 1, and Ar is as generally defined in formula (I).

In still other embodiments, the compound is as represented by formula(Ib), in particular formula (If), (Ih) or (Im), m is 0, and Ar is asgenerally defined in formula (I).

In still other embodiments, the compound is as represented by formula(Ib), in particular formula (If), (Ih) or (Im), m is 1, and Ar is asgenerally defined in formula (I).

In still other embodiments, the compound is as represented by formula(Ic), m is 0, and Ar is as generally defined in formula (I).

In still other embodiments, the compound is as represented by formula(Ic), m is 1, and Ar is as generally defined in formula (I).

In other embodiments, the compound is as represented by formula (Id), inparticular formula (Ij) or (Im), m is 0, and Ar is as generally definedin formula (I).

In still other embodiments, the compound is as represented by formula(Id), in particular formula (Ij) or (Im), m is 1, and Ar is as generallydefined in formula (I).

In some embodiments, the compound is as represented by formula (Ia), inparticular formula (Ie), or formula (Ig), or formula (Ih), (Ij) or (Ik),V is as generally defined in formula (I), and Ar is as represented informula (Iq).

In other embodiments, the compound is as represented by formula (Ia), inparticular formula (Ie), or formula (Ig), or formula (Ih), (Ij) or (Ik),V is as generally defined in formula (I), and Ar is as represented informula (Ir).

In other embodiments, the compound is as represented by formula (Ia), inparticular formula (Ie), or formula (Ig), or formula (Ih), (Ij) or (Ik),V is as generally defined in formula (I), and Ar is as represented informula (Is).

In some embodiments, the compound is as represented by formula (Ib), inparticular formula (If), V is as generally defined in formula (I), andAr is as represented in formula (Iq).

In some embodiments, the compound is as represented by formula (Ib), inparticular formula (If), (Ih) or (Im), V is as generally defined informula (I), and Ar is as represented in formula (Ir).

In some embodiments, the compound is as represented by formula (Ib), inparticular formula (If), (Ih) or (Im), V is as generally defined informula (I), and Ar is as represented in formula (Is).

In still other embodiments, the compound is as represented by formula(Ic), V is as generally defined in formula (I), and Ar is as representedin formula (Iq).

In still other embodiments, the compound is as represented by formula(Ic), V is as generally defined in formula (I), and Ar is as representedin formula (Ir).

In still other embodiments, the compound is as represented by formula(Ic), V is as generally defined in formula (I), and Ar is as representedin formula (Is).

In still other embodiments, the compound is as represented by formula(Id), in particular formula (Ij) or (Im), V is as generally defined informula (I), and Ar is as represented in formula (Iq).

In still other embodiments, the compound is as represented by formula(Id), in particular formula (Ij) or (Im), V is as generally defined informula (I), and Ar is as represented in formula (Ir).

In still other embodiments, the compound is as represented by formula(Id), in particular formula (Ij) or (Im), V is as generally defined informula (I), and Ar is as represented in formula (Is).

Furthermore, in some embodiments, the compound is as represented byformula (Ia), in particular formula (Ie), or formula (Ig), or formula(Ih), (Ij) or (Ik), m is 0, and Ar is as defined in formula (Iq).

In some embodiments, the compound is as represented by formula (Ia), inparticular formula (Ie), or formula (Ig), or formula (Ih), (Ij) or (Ik),m is 0, and Ar is as defined in formula (Ir).

In some embodiments, the compound is as represented by formula (Ia), inparticular formula (Ie), or formula (Ig), or formula (Ih), (Ij) or (Ik),m is 0, and Ar is as defined in formula (Is).

In some other embodiments, the compound is as represented by formula(Ia), in particular formula (Ie), or formula (Ig), or formula (Ih), (Ij)or (Ik), m is 1, and Ar is as defined in formula (Iq).

In some other embodiments, the compound is as represented by formula(Ia), in particular formula (Ie), or formula (Ig), or formula (Ih), (Ij)or (Ik), m is 1, and Ar is as defined in formula (Ir).

In some other embodiments, the compound is as represented by formula(Ia), in particular formula (Ie), or formula (Ig), or formula (Ih), (Ij)or (Ik), m is 1, and Ar is as defined in formula (Is).

In still other embodiments, the compound is as represented by formula(Ib), in particular formula (If), (Ih) or (Im), m is 0, and Ar is asdefined in formula (Iq).

In still other embodiments, the compound is as represented by formula(Ib), in particular formula (If), (Ih) or (Im), m is 0, and Ar is asdefined in formula (Ir).

In still other embodiments, the compound is as represented by formula(Ib), in particular formula (If), (Ih) or (Im), m is 0, and Ar is asdefined in formula (Is).

In still other embodiments, the compound is as represented by formula(Ib), in particular formula (If), (Ih) or (Im), m is 1, and Ar is asdefined in formula (Iq).

In still other embodiments, the compound is as represented by formula(Ib), in particular formula (If), (Ih) or (Im), m is 1, and Ar is asdefined in formula (Ir).

In still other embodiments, the compound is as represented by formula(Ib), in particular formula (If), (Ih) or (Im), m is 1, and Ar is asdefined in formula (Is).

In still other embodiments, the compound is as represented by formula(Ic), m is 0, and Ar is as defined in formula (Iq).

In still other embodiments, the compound is as represented by formula(Ic), m is 0, and Ar is as defined in formula (Ir).

In still other embodiments, the compound is as represented by formula(Ic), m is 0, and Ar is as defined in formula (Is).

In still other embodiments, the compound is as represented by formula(Id), in particular formula (Ij) or (Im), m is 1, and Ar is as definedin formula (Iq).

In still other embodiments, the compound is as represented by formula(Id), in particular formula (Ij) or (Im), m is 1, and Ar is as definedin formula (Ir).

In still other embodiments, the compound is as represented by formula(Id), in particular formula (Ij) or (Im), m is 1, and Ar is as definedin formula (Is).

Studies have shown efficacy of the compounds of the invention in vitroand in vivo in mice and, although the compounds have been developedtoward S100A9 inhibition, they can also show activity to other S100proteins. The present invention therefore relates to compounds asdefined herein, as S100 protein inhibitors, mainly as S100A9 inhibitorsand to their use in treatment or prevention of S100-protein relateddiseases, in particular diseases related to the activity of S100A9protein.

In particular, the present invention relates to the compounds of formula(I) as defined herein, to pharmaceutical compositions comprising saidcompounds, to the use of such compositions in the therapeutic treatmentof conditions selected from in particular cancer, but also automimmunediseases, inflammatory diseases and neurodegenerative diseases, to amethod of treatment of such conditions, and to said compounds for use inthe treatment of conditions selected from in particular cancer, but alsoautomimmune diseases, inflammatory diseases and neurodegenerativediseases, as well as the use of said compounds in the manufacture ofpharmaceutical compositions for the treatment of such conditions.

The present invention includes pharmaceutical compositions comprising atleast one compound according to formula (I), or an individual isomer,racemic or non-racemic mixture of isomers or a pharmaceuticallyacceptable salt thereof, together with at least one pharmaceuticallyacceptable excipient, e.g. a carrier, and optionally other therapeuticand/or prophylactic ingredients.

A pharmaceutical composition according to the invention may be fortopical (local) or systemic administration, e.g for enteraladministration, such as rectal or oral administration, or for parenteraladministration to a mammal (especially a human), and comprises atherapeutically effective amount of a compound according to theinvention or a pharmaceutically acceptable salt thereof, as activeingredient, in association with a pharmaceutically acceptable excipient,e.g. a pharmaceutically acceptable carrier. The therapeuticallyeffective amount of the active ingredient is as defined herein above anddepends e.g. on the species of mammal, the body weight, the age, theindividual condition, individual pharmacokinetic data, the disease to betreated and the mode of administration.

For enteral, e.g. oral, administration, the compounds of the inventionmay be formulated in a wide variety of dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or pharmaceutically acceptable salt(s) thereof asthe active component. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, pills, lozenges, capsules, cachets, suppositories, anddispersible granules. A solid carrier may be one or more substanceswhich may also act as diluents, flavouring agents, solubilizers,lubricants, suspending agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material. In powders, thecarrier generally is a finely divided solid which is a mixture with thefinely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatine, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The formulation of the active compound may comprise an encapsulatingmaterial as carrier, providing a capsule in which the active component,with or without carriers, is surrounded by a carrier, which is inassociation with it.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Exemplary compositions for rectal administration include suppositorieswhich can contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquefy and/ordissolve in the rectal cavity to release the drug.

The compounds of the invention also may be administered parenterally,e.g. by inhalation, injection or infusion, e.g. by intravenous,intraarterial, intraosseous, intramuscular, intracerebral,intracerebroventricular, intrasynovial, intrasternal, intrathecal,intralesional, intracranial, intratumoral, intracutaneous andsubcutaneous injection or infusion.

Thus, for parenteral administration, the pharmaceutical compositions ofthe invention may be in the form of a sterile injectable or infusiblepreparation, for example, as a sterile aqueous or oleaginous suspension.This suspension may be formulated according to techniques known in theart using suitable dispersing or wetting agents (e.g., Tween 80), andsuspending agents. The sterile injectable or infusible preparation mayalso be a sterile injectable or infusible solution or suspension in anon-toxic parenterally acceptable diluent or solvent. For example, thepharmaceutical composition may be a solution in 1,3-butanediol. Otherexamples of acceptable vehicles and solvents that may be employed in thecompositions of the present invention include, but are not limited to,mannitol, water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or diglycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of inj ectables, as are natural pharmaceutically acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant.

Solutions for parenteral use also may contain suitable stabilizingagents, and if necessary, buffer substances. Suitable stabilizing agentsinclude antioxidizing agents, such as sodium bisulfate, sodium sulfiteor ascorbic acid, either alone or combined, citric acid and its saltsand sodium EDTA. Parenteral solutions may also contain preservatives,such as benzalkonium chloride, methyl- or propyl-paraben, andcholorobutanol.

For inhalation or nasal administration, suitable pharmaceuticalformulations are as particles, aerosols, powders, mists or droplets,e.g. with an average size of about 10 μm in diameter or less. Forexample, compositions for inhalataion may be prepared as solutions insaline, employing benzyl alcohol or other suitable preservatives,absorption promoters to enhance bioavailability, fluorocarbons, and/orother solubilizing or dispersing agents known in the art.

The pharmaceutical compositions of the invention also may beadministered topically, to the skin or to a mucous membrane. For topicalapplication, the pharmaceutical composition may be e.g. a lotion, a gel,a paste, a tincture, a transdermal patch, a gel for transmucosaldelivery. The composition may be formulated with a suitable ointmentcontaining the active components suspended or dissolved in a carrier.Carriers for topical administration of the compounds of this inventioninclude, but are not limited to, mineral oil, liquid petroleum, whitepetroleum, propylene glycol, polyoxyethylene polyoxypropylene compound,emulsifying wax and water. Alternatively, the pharmaceutical compositionmay be formulated as a suitable lotion or cream containing the activecompound suspended or dissolved in a carrier. Suitable carriers include,but are not limited to, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, cetaryl alcohol, 2-octyldodecanol, benzyl alcoholand water. The pharmaceutical compositions of this invention may also betopically applied to the lower intestinal tract by rectal suppositoryformulation or in a suitable enema formulation.

Suitable pharmaceutical excipients, e.g. carriers, and methods ofpreparing pharmaceutical dosage forms are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in art of drug formulation.

The pharmaceutical compositions may comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90% of a compound of formula (I), together with at least onepharmaceutically acceptable excipient. In general, the compounds of theinvention will be administered in a therapeutically effective amount byany of the accepted modes of administration for agents that servesimilar utilities. Suitable daily dosages typically ranges from 1 to1000 mg, e.g. 1-500 mg daily, or 1-50 mg daily, depending upon numerousfactors such as the severity of the disease to be treated, the age andrelative health of the patient, the potency of the compound used, theroute and form of administration, and the indication towards which theadministration is directed, etc. One of ordinary skill in the art oftreating such diseases will be able, without undue experimentation andin reliance upon personal knowledge and the disclosure of thisapplication, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease. Compounds of theinvention may be administered as pharmaceutical formulations includingthose suitable for enteral or parenteral administration. The preferredmanner of administration is generally oral using a convenient dailydosage regimen which can be adjusted according to the degree ofaffliction.

According to one aspect, the present invention relates to a method oftreatment of a disease that responds to inhibition of a member of theS100 protein family, e.g. S100A9, e.g. a cancer, an autoimmune disease,an inflammatory disease, or a neurodegenerative disease, which methodcomprises administering a therapeutically effective amount of a compoundof formula (I), or pharmaceutically acceptable salt thereof, to awarm-blooded animal, e.g., a human, in need of such treatment.

In some embodiments, the disorder treated according to the presentinvention is a cancer, e.g. a cancer such as defined herein above.

In some other embodiments, the disorder treated according to the presentinvention is an automimmune disorder, e.g. and automimmune disorder suchas defined herein above.

In some other embodiments, the disorder treated according to the presentinvention is an an inflammatory disorder, e.g. an inflammatory disordersuch as defined herein above.

In some other embodiments, the disorder treated according to the presentinvention is an neurodegenerative disorder, e.g. a neurodegenerativedisorder such as defined herein above.

The preparation of compounds within the scope of formula (I) is wellwithin the capacity of the person of ordinary skill in the art. Forexample, a compound of formula (I) may be prepared by reacting asulfonyl chloride 1 with an amine 2 in a suitable solvent medium, as asillustrated in the following reaction scheme:

If necessary, the hydroxy group of amine 2 may be protected during thecoupling reaction, e.g. as a methoxy group.

The following examples will enable a person skilled in the art to moreclearly understand and practice the present invention. These examples,however, should not be considered as limiting the scope of theinvention, but merely as being illustrative and representative thereof.

EXAMPLES

All pyridine used was stored over activated 4 Å mol sieves.

“Low pH method” refers to HPLC purification using a mobile phaseconsisting of 0.2% formic acid in a gradient of 0-100% MeCN in water.The stationary phase consisted of a Waters Sunfire C18 column, 10 mparticle size, 30×100 mm.

“High pH method” refers to HPLC purification using a mobile phaseconsisting of 0.2% ammonia in a gradient of 0-100% MeCN in water. Thestationary phase consisted of a Waters X-bridge C18 column, 10 mparticle size, 30×100 mm.

SFC was carried out using a Chiralpak AD-H column with a mobile phase ofsupercritical CO₂ and methanol containing 0.1% formic acid.

General Procedure for Coupling Sulfonyl Chlorides to Methoxy- or HydroxySubstituted Aminopyridines, Procedure A:

To an ice-cooled solution of the methoxy- or hydroxy substitutedaminopyridine (1 mmol, in dichloromethane (4 mL) and pyridine (4 mmol),was added dropwise a solution of sulfonyl chloride (1.2 mmol) dissolvedin dichloromethane (2 mL). The mixture was allowed to stir at roomtemperature until TLC (heptane/ethyl acetate/acetic acid 1:3:0.16) showcomplete disappearance of the aminopyridine (ususally 1-18 hours).Samples for TLC were taken out from the mixture and shaken with amixture of ethyl acetate and water. TLC was run on the organic phase.When TLC indicated complete reaction the mixture was concentrated on arotary evaporator, then dissolved in a mixture of ethanol (5 mL) andNaOH (1 M, 2 mL) and heated at 60° C. for 2 hours. The mixture was thencooled and acetic acid (0.5 mL) was added which usually results inprecipitation of the desired product. If there was no precipitation themixture was instead partitioned between ethyl acetate and water, theorganic phase was concentrated and the residue was purified by flashchromatography (silica, ethyl acetate/heptane mixtures).

General Procedure for the Cleavage of the Methoxy Group to PrepareHydroxy Substituted Sulfonamides, Procedure B:

To 1 mmol methoxy-substituted compound (achieved using procedure A) wasadded 4 mL dichloromethane under nitrogen, the mixture was cooled in anice-bath and BBr₃ (1 M solution in CH₂Cl₂, 2 equiv., 2 mL) was addeddropwise. The cooling bath was removed and the mixture was stirred untilTLC (heptane/ethyl acetate/acetic acid 1:3:0.16) showed completedisappearance of methoxy compound (usually 2-4 hours). Eventually oneextra equiv. BBr₃ was added to complete the reaction. When the reactionwas complete the mixture was cooled in an ice bath and 1 mL1,2-propanediol was added (exothermic!) followed by the addition of 5 mLn-propanol. The mixture was concentrated to remove dichloromethane, thendiluted with n-propanol (5 mL) and 0.5 ml 5 M HCl and heated at 80° C.until the mixture gets clear. Then the mixture was cooled to room tempand water was added to precipitate the desired product. The precipitatewas filtered, dried and recrystallized. Recrystallization was performedby dissolving the material in a mixture of 5 mL ethanol and approx. 2 mL1M NaOH to pH>11, any insolubilities were filtered off and the mixturewas acidified by addition of HCl or acetic acid. Eventually water wasadded to initiate the crystallization. Alternatively, recrystallizationwas achieved by dissolving in hot acetic acid and precipitation withwater. If there was no solid precipitation after the heating step at 80°C. and addition of water the mixture was extracted with ethyl acetateand purified by flash chromatography (SiO2, ethyl acetate/heptanemixtures).

Non-commercial sulfonyl chlorides or methoxy- or hydroxy substitutedaminopyridines were prepared using literature methods or the methodsdescribed in this patent application.

Intermediates6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide

To a solution of 5-chloro-3-methoxypyridin-2-amine (1.50 g, 9.46 mmol),prepared according to literature (Int. Appl. No. PCT/US2011/020414;Publ. No. WO 2011085126) in pyridine (15 mL) was added6-chloropyridine-3-sulfonyl chloride hydrochloride (2.35 g, 9.46 mmol)and the solution stirred at room temperature for 64 hrs. The solvent wasevaporated and the mixture partitioned between DCM (60 mL) and water (20mL). The phases were separated and the organic phase was washed withbrine (20 mL), dried (Na₂SO₄), the mixture was filtered and the filtrateevaporated to dryness to afford a purple solid which was chromatographedon silica (100 g SNAP column, eluting with 15-40% EtOAc in heptane),affording6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide as anorange oil (360 mg, 11%); m/z 333.8, 335.8 (MH)⁺.

3-methoxy-2-nitro-5-(prop-1-en-2-yl)pyridine

To a solution of 5-bromo-3-methoxy-2-nitropyridine (1.30 g, 5.58 mmol),prepared by a literature method (Int. Appl. No. PCT/EP2010/052589; Publ.No. WO 2010100127) in a mixture of 1,4-dioxane (13 mL) and water (5 mL)were added potassium isopropenyl trifluoroborate (908 mg, 6.14 mmol),caesium carbonate (5.46 g, 16.7 mmol) and1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloridedichloromethane complex (70 mg, 0.086 mmol) and the mixture was stirredat 70° C. for 1 hr under a nitrogen atmosphere. Brine (10 mL) and EtOAc(50 mL) were then added. The phases were separated and the organic phasewas washed with brine (5 mL), dried (Na₂SO₄), the mixture was filteredand the filtrate evaporated to dryness to afford an orange oil which waschromatographed on silica (heptane/EtOAc 4:1) to afford3-methoxy-2-nitro-5-(prop-1-en-2-yl)pyridine as a yellow solid (740 mg,68%); m/z=195.0 (MH)⁺.

3-methoxy-5-(propan-2-yl)pyridin-2-amine

A solution of 3-methoxy-2-nitro-5-(prop-1-en-2-yl)pyridine (250 mg, 1.29mmol) in EtOH (10 mL) was treated with 10% Pd/C (25 mg), degassed threetimes under nitrogen/vacuum and hydrogenated for 3 hrs at atmosphericpressure. The mixture was filtered through Celite and the filtrateevaporated to dryness to afford 3-methoxy-5-(propan-2-yl)pyridin-2-amineas a purple oil (240 mg at 78% purity, 87% yield); m/z=167.0 (MH)⁺.

(+/−)-2-(5-methoxy-6-nitropyridin-3-yl)propan-1-ol

A solution of 3-methoxy-2-nitro-5-(prop-1-en-2-yl)pyridine (400 mg, 2.06mmol) in THF (10 mL) was stirred at 0° C. Borane dimethylsulfide complex(2M in THF, 1.54 mL, 3.08 mmol) was added and the mixture was allowed towarm to room temperature and stirred for 1 hr. 30% hydrogen peroxide(2.3 mL, 20 mmol) was then added dropwise, followed by 5M sodiumhydroxide solution (2.0 mL, 10 mmol), also dropwise. CAUTION-rapideffervesence and exotherm occurred. The mixture was stirred for 30 minand partitioned between EtOAc and further 5M NaOH. The phases wereseparated and the organic phase was washed with brine (20 mL), dried(Na₂SO₄), the mixture was filtered and the filtrate evaporated todryness to afford an orange oil which was chromatographed on silica(heptane:EtOAc 1:1) to afford(+/−)-2-(5-methoxy-6-nitropyridin-3-yl)propan-1-ol as a colourless oil(170 mg, 39%); m/z=212.9 (MH)⁺.

(+/−)-2-(6-amino-5-methoxypyridin-3-yl)propan-1-ol

A solution of (+/−)-2-(5-methoxy-6-nitropyridin-3-yl)propan-1-ol (170mg, 0.801 mmol) in EtOH (10 mL) was treated with 10% Pd/C (30 mg),degassed three times under nitrogen/vacuum then hydrogenated for 16 hrsat room temperature. The mixture was filtered through Celite and thefiltrate evaporated to dryness to afford(+/−)-2-(6-amino-5-methoxypyridin-3-yl)propan-1-ol as a yellow oil (130mg, 89%); m/z=182.9 (MH)⁺.

5-bromo-6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide

To a solution of 2-amino-5-chloro-3-methoxypyridine (1.00 g, 4.92 mmol)in pyridine (10 mL) was added 5-bromo-6-chloropyridine-3-sulfonylchloride (2.00 g, 6.89 mmol) and the mixture was stirred at roomtemperature for 1 h. The solvent was evaporated and purification of theresidue carried out by silica chromatography to afford 50% pure5-bromo-6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide,contaminated with starting amine (1.84 g at 50% purity, 45%); m/z=411.6,413.6.

1-{[(2,5-dichlorothiophen-3-yl)methyl]sulfanyl}ethan-1-one

To a solution of 3-(bromomethyl)-2,5-dichlorothiophene (3.60 g, 14.6mmol), prepared by a literature procedure (Int. Appl. No.PCT/CA2010/000779; Publ. No. WO 2010132999) in acetone (150 mL) wasadded potassium carbonate (6.07 g, 43.9 mmol) and thioacetic acid (1.34g, 17.6 mmol) and the mixture refluxed 45 min. The solvent wasevaporated then DCM (100 mL) and water (15 mL) were added to theresidue. The phases were separated and the organic phase was washed withbrine (10 mL), dried (Na₂SO₄), the mixture was filtered and the filtrateevaporated to dryness to afford1-{[(2,5-dichloro-thiophen-3-yl)methyl]sulfanyl}ethan-1-one as a brownoil (3.53 g, 97%); ¹H NMR (500 MHz, CDCl₃) δ 2.27 (s, 3H), 3.90 (s, 2H),6.65 (s, 1H).

(2,5-dichlorothiophen-3-yl)methanesulfonyl Chloride

A solution of 1-{[(2,5-dichlorothiophen-3-yl)methyl]sulfanyl}ethan-1-one(130 mg, 0.518 mmol) in a mixture of AcOH (2.2 mL) and water (0.3 mL) atroom temperature was saturated with chlorine gas and stirred until thedisappearance of starting material was observed by TLC. The reactionmixture was diluted with EtOAc (50 mL) and brine (20 mL). The phaseswere separated and the organic phase was washed with brine (2×10 mL),dried (Na₂SO₄), the mixture was filtered and the filtrate evaporated todryness to afford (2,5-dichlorothiophen-3-yl)methanesulfonyl chloride asa yellow oil (130 mg, 82%); ¹H NMR (500 MHz, CDCl₃) δ 4.74 (s, 2H), 6.92(s, 1H).

1-{[(3-chloro-5-fluorophenyl)methyl]sulfanyl}ethan-1-one

The procedure for the preparation of1-{[(2,5-dichlorothiophen-3-yl)methyl]-sulfanyl}ethan-1-one was used,except that 1-(bromomethyl)-3-chloro-5-fluorobenzene was substituted for3-(bromomethyl)-2,5-dichlorothiophene (97% yield); ¹H NMR (250 MHz,CDCl₃) δ 2.37 (s, 3H), 4.05 (s, 2H), 6.94 (m, 2H), 7.08 (s, 1H).

(3-chloro-5-fluorophenyl)methanesulfonyl chloride

The procedure for the preparation of(2,5-dichlorothiophen-3-yl)methanesulfonyl chloride was used, exceptthat 1-{[(3-chloro-5-fluorophenyl)methyl]sulfanyl}ethan-1-one wassubstituted for1-{[(2,5-dichlorothiophen-3-yl)methyl]sulfanyl}ethan-1-one (80% yield);¹H NMR (500 MHz, CDCl₃) δ 4.83 (s, 2H), 7.16 (m, 1H), 7.25 (m, 1H), 7.31(s, 1H).

3-methoxy-5-(methylsulfanyl)-2-nitropyridine

To a solution of 5-bromo-3-methoxy-2-nitropyridine (2.00 g, 8.58 mmol)in DMF (10 mL) was added sodium methanethiolate (541 mg, 7.72 mmol) inportions so that the temperature did not rise above 30° C. More sodiummethanethiolate (155 mg, 2.21 mmol) was added in an attempt to drive thereaction to completion. Water (100 mL) was added followed by EtOAc (300mL). The phases were separated and the organic phase was washed withwater (2×20 mL) and brine (20 mL), dried (Na₂SO₄), the mixture wasfiltered and the filtrate evaporated to dryness to afford a brown oilwhich was chromatographed on silica (eluent: heptane:EtOAc 3:1 fallingto 2:1) to afford 3-methoxy-5-(methylsulfanyl)-2-nitropyridine as anorange solid (307 mg, 18%); m/z=200.9.

3-methoxy-5-(methylsulfanyl)pyridin-2-amine

To a suspension of 3-methoxy-5-(methylsulfanyl)-2-nitropyridine (220 mg,1.10 mmol) in EtOH (15 mL) was added anhydrous tin(II) chloride (870 mg,4.40 mmol) and the mixture heated at 90° C. for 2 hrs. The solvent wasevaporated and the residue was partitioned between DCM (100 mL) and 2MNaOH (60 mL). The phases were separated and the organic phase was washedwith more 2M NaOH (20 mL), brine (20 mL), dried (Na₂SO₄), the mixturewas filtered and the filtrate evaporated to dryness to afford3-methoxy-5-(methylsulfanyl)pyridin-2-amine as a yellow oil whichcrystallized on standing (96% yield); m/z=170.9.

1-{[(5-chloro-2-fluorophenyl)methyl]sulfanyl}ethan-1-one

The procedure for the preparation of1-{[(2,5-dichlorothiophen-3-yl)methyl]sulfanyl})-ethan-1-one was used,except that 1-(bromomethyl)-5-chloro-2-fluorobenzene was substituted for3-(bromomethyl)-2,5-dichlorothiophene (82%); ¹H NMR (400 MHz, CDCl₃) δ2.36 (s, 3H), 4.09 (d, 2H), 6.97 (m, 1H), 7.18 (ddd, 1H), 7.35 (dd, 1H).

(5-chloro-2-fluorophenyl)methanesulfonyl chloride

To a stirred solution of N-chlorosuccinimide (855 mg, 6.44 mmol) inacetonitrile (5 mL) was added 2M HCl (5 drops) and the reaction mixturecooled to 0° C. To this mixture was added a solution of1-{[(5-chloro-2-fluorophenyl)methyl]sulfanyl}ethan-1-one (350 mg, 1.60mmol) in acetonitrile (1 mL) and the resultant reaction mixture wasstirred at 0° C. On disappearance of starting material (as judged byTLC), the solvent was evaporated and(5-chloro-2-fluorophenyl)methanesulfonyl chloride was used crude in thenext step (98%).

(+/−)-1-(3,5-dichlorophenyl)ethan-1-ol

To a solution of 1-(3,5-dichlorophenyl)ethan-1-one (1.00 g, 5.29 mmol)in EtOH (10 mL) at room temperature was added solid NaBH₄ (100 mg, 2.64mmol) in three portions over 5 min with stirring. The solvent wasevaporated and the resultant white solid treated with 1M HCl (20 mL) andDCM (70 mL). The phases were separated and the organic phase was washedwith brine (20 mL), dried (Na₂SO₄), the mixture was filtered and thefiltrate evaporated to dryness to afford(+/−)-1-(3,5-dichlorophenyl)ethan-1-ol as a cloudy oil (1025 mg, 100%);¹H NMR (250 MHz, CDCl₃) δ 1.47 (d, 3H), 4.85 (q, 1H), 7.24-7.28 (m, 3H).

(+/−)-1-{[1-(3,5-dichlorophenyl)ethyl]sulfanyl}ethan-1-one

To a solution of (+/−)-1-(3,5-dichlorophenyl)ethan-1-ol (650 mg, 3.40mmol) in DCM (5 mL) was added phosphorus tribromide (967 mg, 3.57 mmol)and the mixture was stirred for 15 min. More DCM was added (30 mL)followed by saturated NaHCO₃ (15 mL). The phases were separated and theorganic phase was washed with brine (5 mL), dried (Na₂SO₄), the mixturewas filtered and the filtrate evaporated to dryness to afford the crudebromide which was immediately dissolved in acetone (15 mL), thioaceticacid added (285 mg, 3.74 mmol) followed by K₂CO₃ (705 mg, 5.10 mmol) andthe mixture was stirred at 50° C. for 1 h. The solvent was evaporatedand DCM (60 mL) and saturated K₂CO₃ was added (15 mL). The phases wereseparated and the organic phase was washed with brine (5 mL), dried(Na₂SO₄), the mixture was filtered and the filtrate evaporated todryness to afford a brown oil which was chromatographed (heptane:EtOAc12:1) to afford(+/−)-1-{[1-(3,5-dichlorophenyl)ethyl]sulfanyl}ethan-1-one as an orangeoil (310 mg, 37%); ¹H NMR (250 MHz, CDCl₃) δ 1.54 (d, 3H), 2.24 (s, 3H),4.58 (q, 1H), 7.13-7.18 (m, 3H).

(+/−)-1-(3,5-dichlorophenyl)ethane-1-sulfonyl chloride

The procedure for the preparation of(2,5-dichlorothiophen-3-yl)methanesulfonyl chloride was used, exceptthat (+/−)-1-{[1-(3,5-dichlorophenyl)ethyl]sulfanyl}ethan-1-one wassubstituted for1-{[(2,5-dichlorothiophen-3-yl)methyl]sulfanyl}ethan-1-one (245 mg,75%); no data taken as material was used immediately in the next step.5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide5-chloro-3-methoxypyridin-2-amine (200 mg, 1.26 mmol) and5-bromopyridine-3-sulfonyl chloride (350 mg, 1.39 mmol) were combined ina sealed tube and heated at 110° C. for 16 hrs. The reaction mixture wasdissolved in 10% methanol in DCM (10 mL) and the solvent evaporated toyield a brown residue which was chromatographed on silica (eluent:acetone:DCM, 1:9) to afford5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)-pyridine-3-sulfonamide (60mg, 12%) as an off-white solid; m/z=378.3, 380.3 (MH)⁺.

N-(5-chloro-3-methoxypyridin-2-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide

The procedure for preparation ofN-(5-chloro-3-methoxypyridin-2-yl)-1-methyl-1H-imidazole-4-sulfonamidewas used, except that 3-(trifluoromethoxy)benzenesulfonyl chloride wassubstituted for 1-methyl-1H-imidazole-4-sulfonyl chloride.Chromatography on silica (eluent: MeOH:DCM, 1:19 containing 1% aq.ammonia) affordedN-(5-chloro-3-methoxypyridin-2-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide(100 mg, 28%) as a white solid; m/z=383.3, 385.3 (MH)⁺.

5-bromo-3-methoxypyridin-2-amine

To a solution of 3-methoxypyridin-2-amine (1.00 g, 8.06 mmol) in aceticacid (10 mL) was added bromine (0.414 mL, 8.06 mmol) over 30 min. Thereaction mixture was then stirred at room temperature for 18 hrs. Aceticacid was evaporated in vacuo and the pH of the residue was adjusted to7-8 by slow addition of a saturated aqueous solution of sodiumbicarbonate. The mixture was extracted with ethyl acetate (2×50 mL) andthe combined organic phases dried (Na₂SO₄), filtered and concentrated toafford a crude residue which was triturated in ethyl acetate andn-pentane to afford 5-bromo-3-methoxy-pyridin-2-amine (750 mg, 46%) as ared solid. ¹H NMR (400 MHz, CDCl₃) δ 3.85 (d, 3H), 4.69 (s, 2H), 7.00(d, 1H), 7.71 (d, 1H).

N-(5-bromo-3-methoxypyridin-2-yl)benzene sulfonamide

The procedure for preparation ofN-(5-chloro-3-methoxypyridin-2-yl)-2,4-dimethyl-1,3-thiazole-5-sulfonamidewas used except that benzenesulfonyl chloride was substituted fordimethyl-1,3-thiazole-5-sulfonyl chloride and5-bromo-3-methoxypyridin-2-amine substituted for5-chloro-3-methoxypyridin-2-amine. The crude product was purified bytrituration in ethyl acetate and n-hexane to yieldN-(5-bromo-3-methoxypyridin-2-yl)-benzene sulfonamide (100 mg, 60%) asan off-white solid; ¹H NMR (400 MHz, CDCl₃) δ 3.85 (s, 3H), 7.14 (d,1H), 7.50 (dd, 2H), 7.54-7.62 (m, 2H), 7.89 (d, J=1H), 8.11-8.17 (m,2H).

N-(5-bromo-3-methoxypyridin-2-yl)-2,5-dichlorothiophene-3-sulfonamide

The procedure for preparation ofN-(5-bromo-3-methoxypyridin-2-yl)benzene sulfonamide was used exceptthat 2,5-dichlorothiophene-3-sulfonyl chloride was substituted forbenzenesulfonyl chloride.

N-(5-bromo-3-methoxypyridin-2-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide

The procedure for preparation ofN-(5-chloro-3-methoxypyridin-2-yl)-1-methyl-1H-imidazole-4-sulfonamidewas used, except that 3-(trifluoromethoxy)benzenesulfonyl chloride wassubstituted for 1-methyl-1H-imidazole-4-sulfonyl chloride and5-bromo-3-methoxypyridin-2-amine substituted for5-chloro-3-methoxypyridin-2-amine. Purification was carried out bychromatography on silica (eluent: MeOH:DCM, 1:9 containing 1% aq.ammonia) to affordN-(5-bromo-3-methoxypyridin-2-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide(44%) as a brown solid; m/z=427.3, 429.3 (MH)⁺.

N-(5-bromo-3-methoxypyridin-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

The procedure for preparation ofN-(5-chloro-3-methoxypyridin-2-yl)-2,4-dimethyl-1,3-thiazole-5-sulfonamidewas used except that 6-(trifluoromethyl)pyridine-3-sulfonyl chloride wassubstituted for dimethyl-1,3-thiazole-5-sulfonyl chloride and5-bromo-3-methoxypyridin-2-amine substituted for5-chloro-3-methoxypyridin-2-amine. The crude compound waschromatographed on silica (eluent: EtOAc:Hexane, 3:7) to yieldN-(5-bromo-3-hydroxypyridin-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide(58%) as an off-white solid; m/z=412.3, 414.3 (MH)⁺.

5-bromo-N-(5-bromo-3-methoxypyridin-2-yl)-6-chloropyridine-3-sulfonamide

The procedure for preparation ofN-(5-chloro-3-methoxypyridin-2-yl)-2,4-dimethyl-1,3-thiazole-5-sulfonamidewas used except that 5-bromo-6-chloropyridine-3-sulfonyl chloride wassubstituted for dimethyl-1,3-thiazole-5-sulfonyl chloride and5-bromo-3-methoxypyridin-2-amine substituted for5-chloro-3-methoxypyridin-2-amine. The crude compound waschromatographed on silica (eluent: EtOAc:Hexane, 3:7) to yield5-bromo-N-(5-bromo-3-methoxypyridin-2-yl)-6-chloropyridine-3-sulfonamide(41%) as an off-white solid; m/z=458.0, 460.0 (MH)⁺.

N-(3-methoxypyridin-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

The procedure for preparation ofN-(5-chloro-3-methoxypyridin-2-yl)-1-methyl-1H-imidazole-4-sulfonamidewas used, except that 6-(trifluoromethyl)pyridine-3-sulfonyl chloridewas substituted for 1-methyl-1H-imidazole-4-sulfonyl chloride and3-methoxy-pyridin-2-amine substituted for5-chloro-3-methoxypyridin-2-amine. Chromatography on silica (eluent:Methanol:DCM, 3:97) affordedN-(3-methoxypyridin-2-yl)-6-(trifluoro-methyl)pyridine-3-sulfonamide(13%) as an off-white solid; m/z=334.4 (MH)⁺.

Methyl 6-amino-5-methoxypyridine-3-carboxylate

In a sealable tube, 5-hydroxypyridine-3-carboxylic acid (1.00 g, 5.95mol) was dissolved in concentrated H₂SO₄ (1.34 mL). Then fuming nitricacid (1.35 mL) was added drop wise at 0-5° C. and the reaction mixturebrought to room temperature slowly and stirred for 16 hrs before beingpoured onto ice cold water. The pH was adjusted to 3 with 50% NaOHsolution and then extracted with isopropyl alcohol:chloroform (1:19,4×45 mL). After separation of layers and removal of solvent underreduced pressure, a pale yellow solid was obtained (1.2 g), consistingof a mixture of starting material and5-hydroxy-6-nitropyridine-3-carboxylic acid in a 2:3 ratio.

This mixture was dissolved in DMF (7 mL) and K₂CO₃ (1.50 g, 10.9 mmol)was added. The reaction mixture was stirred at room temperature for 15min, cooled to 5-10° C. and methyl iodide (0.680 mL, 10.9 mmol) as asolution in DMF (3 mL) was added slowly. The reaction mixture wasstirred at room temperature for 3 more hours, then poured into ice coldwater. A yellow solid precipitated, which was filtered and washedsequentially with water then hexanes and dried under vacuum to affordmethyl 5-methoxy-6-nitropyridine-3-carboxylate (0.5 g, 43%) as a yellowsolid.

To a solution of methyl 5-methoxy-6-nitropyridine-3-carboxylate (1 g,4.71 mmol) in methanol, iron powder (390 mg, 7.07 mmol) and acetic acid(3.8 mL) were added and the reaction mixture was stirred for 3 hrs. Theresultant mixture was concentrated to near dryness, 30% ammoniumhydroxide solution (18 mL) was added and the aqueous phase was extractedwith ethyl acetate (3×50 mL). The combined organic phases were dried(Na₂SO₄), concentrated and the crude compound triturated with n-pentaneto afford methyl 6-amino-5-methoxypyridine-3-carboxylate (0.5 g, 58%) asa red solid, m/z 183.3 (MH)⁺.

Methyl6-(2,5-dichlorothiophene-3-sulfonamido)-5-methoxypyridine-3-carboxylate

The procedure used to prepareN-(5-chloro-3-methoxypyridin-2-yl)-2,4-dimethyl-1,3-thiazole-5-sulfonamidewas used, except that 2,5-dichlorothiophene-3-sulfonyl chloride wassubstituted for dimethyl-1,3-thiazole-5-sulfonyl chloride and methyl6-amino-5-methoxypyridine-3-carboxylate was substituted for5-chloro-3-methoxypyridin-2-amine. The crude product was chromatographedon silica (eluent: EtOAc:Hexane, 2:8) to yield methyl6-(2,5-dichlorothiophene-3-sulfonamido)-5-methoxypyridine-3-carboxylate(40%) as a grey solid; m/z=397.3, 399.3 (MH)⁺.

Methyl 6-benzenesulfonamido-5-methoxypyridine-3-carboxylate

The procedure used to prepareN-(5-chloro-3-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-4-sulfonamidewas used, except that benzenesulfonyl chloride was substituted for1-methyl-1H-pyrazole-4-sulfonyl chloride and methyl6-amino-5-methoxypyridine-3-carboxylate substituted for5-chloro-3-methoxypyridin-2-amine. The crude compound waschromatographed on silica (eluent: EtOAc:Hexane, 2:8) to afford methyl6-benzene-sulfonamido-5-methoxypyridine-3-carboxylate (68%) as a greysolid; ¹H NMR (400 MHz, CDCl₃) δ 3.89 (s, 3H), 3.91 (s, 3H), 7.46-7.61(m, 5H), 8.17 (d, 2H), 8.46 (s, 1H).

N-(5-chloro-2-methoxypyridin-3-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide

The procedure to prepareN-(5-chloro-3-methoxypyridin-2-yl)-1-methyl-1H-imidazole-4-sulfonamidewas used, except that 5-chloro-2-methoxypyridin-3-amine, preparedaccording to literature (Int. Appl. No. PCT/EP2010/062300; Publ. No. WO2011023677), was substituted for 5-chloro-3-methoxypyridin-2-amine and3-(trifluoromethoxy)-benzenesulfonyl chloride was substituted for1-methyl-1H-imidazole-4-sulfonyl chloride. The crude product waschromatographed on silica (eluent: MeOH:DCM, 1:19 containing 1% aq.ammonia) to affordN-(5-chloro-2-methoxypyridin-3-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide(28%) as a white solid; m/z=381.3, 383.3 (MH)⁺.

N-(5-chloro-2-methoxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

The procedure to prepareN-(5-chloro-3-methoxypyridin-2-yl)-2,4-dimethyl-1,3-thiazole-5-sulfonamidewas used, except that 5-chloro-2-methoxypyridin-3-amine was substitutedfor 5-chloro-3-methoxypyridin-2-amine and6-(trifluoromethyl)pyridine-3-sulfonyl chloride was substituted fordimethyl-1,3-thiazole-5-sulfonyl chloride. The crude product waschromatographed on silica (eluent: MeOH:DCM, 1:19) to yieldN-(5-chloro-2-methoxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide(42%) as a grey solid; m/z=368.3, 370.3 (MH)⁺.

5-bromo-6-chloro-N-(5-chloro-2-methoxypyridin-3-yl)pyridine-3-sulfonamide

The procedure used to prepareN-(5-chloro-3-methoxypyridin-2-yl)-2,4-dimethyl-1,3-thiazole-5-sulfonamidewas used, except that 5-bromo-6-chloropyridine-3-sulfonyl chloride wassubstituted for dimethyl-1,3-thiazole-5-sulfonyl chloride and5-chloro-2-methoxypyridin-3-amine was substituted for5-chloro-3-methoxypyridin-2-amine. The crude product was chromatographedon silica (eluent: 0-30% EtOAc in hexanes) to afford5-bromo-6-chloro-N-(5-chloro-2-methoxypyridin-3-yl)pyridine-3-sulfonamideas an off-white solid; m/z 412.2, 414.2 (MH)⁺.

5-iodo-3-methoxypyridin-2-amine

To a solution of 3-methoxypyridin-2-amine (20 g, 160 mmol) in a mixtureof acetic acid (200 mL) and water (20 mL) was added solid I₂ (41 g, 160mmol) and the mixture heated at 50° C. for 1 hr. Another 20 g of iodinewas added and the mixture heated for a further 4 hrs. To the cooledreaction mixture was added EtOAc (1 L) and 1M sodium thiosulfate (3×400mL). The phases were separated and the organic phase was washed withbrine (3×200 mL), dried (Na₂SO₄), the mixture filtered and the filtrateevaporated to dryness to afford a brown oil containing the desiredproduct, which was purified by flash silica chromatography (eluent 3:7EtOAc:hexane) to obtain the title compound as a yellow solid (5.5 g,14%); ¹H NMR (400 MHz, DMSO) δ 3.76 (s, 3H), 5.91 (s, 2H), 7.20 (d, 1H),7.65 (d, 1H).

1-(3,5-dichlorophenyl)-N-(5-iodo-3-methoxypyridin-2-yl)methanesulfonamide

To a stirred solution of 5-iodo-3-methoxypyridin-2-amine (4.8 g, 0.019mol) in pyridine (50 mL) was added (3,5-dichlorophenyl)methanesulfonylchloride (5.0 g, 0.019 mol) and the reaction mixture stirred for 16 hrsthen diluted with water and extracted with EtOAc (3×150 mL). Thecombined organic layers were washed with water and brine, the organiclayer was dried (Na₂SO₄), the mixture was filtered and the filtrateconcentrated to dryness to obtain the crude product which was purifiedby silica chromatography (eluent: 20% EtOAc in hexane) to afford thetitle compound as a yellow solid (5.5 g, 60%); m/z=471.3, 473.3 (MH)⁺.

1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)pyridin-2-yl]methane-sulfonamide

A stirred solution of1-(3,5-dichlorophenyl)-N-(5-iodo-3-methoxypyridin-2-yl)methane-sulfonamide(1.00 g, 2.11 mmol), propane-2-thiol (161 mg, 2.11 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (123 mg, 0.211mmol) in 1,4-dioxane (30 mL) was degassed for 15 min by running a streamof nitrogen through the solution. DIPEA (547 mg, 4.23 mmol) was addedfollowed by (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one—palladium (3:2) (61mg, 0.05 mmol) and the mixture degassed for a further 5 min before beingheated at 90° C. for 16 hrs. The mixture was cooled and filtered thenthe filtrate was concentrated to obtain crude product which wasdissolved in EtOAc and washed with water then saturated brine. Theorganic layer was dried (Na₂SO₄), the mixture was filtered and thefiltrate concentrated to dryness to obtain the title compound as a brownsolid (790 mg, 89%). m/z=421.4, 423.4 (MH)⁺.

1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)pyridin-2-yl]methane-sulfonamide

To a stirred solution of1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)pyridin-2-yl]methanesulfonamide(750 mg, 1.78 mmol) in CHCl₃ (5 mL) was added portionwise solid mCPBA(523 mg, 3.03 mmol). And the reaction mixture stirred at roomtemperature for 16 hrs. The mixture was then diluted with CHCl₃ (50 mL),washed with water (25 mL) and sat. NaHCO₃ (2×25 mL) and the organiclayer was dried over sodium sulfate, the mixture filtered and thefiltrate evaporated to dryness to afford the crude product which waspurified by flash silica chromatography, (eluent 10-50% EtOAc in hexaneto remove the benzoic acid products followed by 1% MeOH in DCM, to elutethe compound which was isolated as an off white solid (550 mg, 68%); ¹HNMR (400 MHz, CDCl₃) δ 1.36 (d, J=6.9 Hz, 6H), 3.26 (m, 1H), 3.95 (s,3H), 4.86 (s, 2H), 7.22 (d, 2H), 7.38 (s, 1H), 7.44 (s, 1H), 7.51 (d,J=8.2 Hz, 1H), 8.49 (s, 1H).

4,6-dibromopyridazin-3-amine and 4-bromo-6-iodopyridazin-3-amine

To a mixture of 6-iodopyridazin-3-amine (500 mg, 2.26 mmol), NaHCO₃ (230mg, 2.71 mmol) in MeOH (5 mL) was added bromine (117 μl, 2.26 mmol)dropwise. The resulting mixture was stirred at room temperature for 16hrs. The solution was filtered and the filtrate concentrated in vacuo.The residue was dissolved in water, and the product extracted with EtOAc(3 times). The organic layers were combined, dried (Na₂SO₄) andconcentrated in vacuo to give a dark red solid which was purified byflash silica chromatography (eluent: 20% EtOAc:Hexane) to give a 60:40mixture of the title compounds as an off white solid (250 mg); H NMR(400 MHz, CDCl₃) δ 5.49 (s, 4H), 7.66 (s, 1H), 7.81 (s, 1H).

6-bromo-4-methoxypyridazin-3-amine and 6-iodo-4-methoxypyridazin-3-amine

To a stirred solution of a mixture of 4,6-dibromopyridazin-3-amine and4-bromo-6-iodopyridazin-3-amine (10 g, compounds not separated inprevious step, estimated 34 mmol) in methanol (90 mL) was added solidsodium methoxide (3.6 g, 67 mmol) at room temperature and the reactionmixture stirred at 90° C. for 16 hrs. More sodium methoxide was addedregularly until all starting material had been consumed. The cooledsolution was concentrated in vacuo and the residue poured into water(200 mL). The resulting solution was extracted with EtOAc three timesand the organic layers were combined, dried (MgSO₄), and concentrated invacuo. The residue was purified by silica column chromatography (eluent:chloroform:methanol (98:0.2 to 90:10) to afford the title mixture ofmethoxy ethers (3.0 g, taken into next steps without furtherpurification); ¹H NMR (400 MHz, CDCl₃) δ 3.90 (s, 3H), 3.92 (s, 3H),5.05 (m, 3H), 6.75 (s, 1H), 6.91 (s, 1H).

4-chloro-3-(hydroxymethyl)benzonitrile

To a stirring solution of 4-chloro-3-formylbenzonitrile (5.00 g, 30.2mmol) in ethanol (50 mL), NaBH4 (571 mg, 15.1 mmol) was added batch-wiseover 1 minute under stirring at room temperature. After 1 hr, thereaction mixture was concentrated in vacuo to afford an off-white solid,treated with 2M HCl (200 mL) and DCM (260 mL), effervescence anddissolution occurred. The layers were separated, the organic layer wasdried over Na₂SO₄, the mixture filtered and concentrated in vacuo toafford the title compound (4.86 g, 96%) as an off-white solid; ¹H NMR(500 MHz, DMSO) δ 4.58 (d, 2H), 5.63 (t, 1H), 7.65 (d, 1H), 7.78 (dd,1H), 7.85-7.94 (m, 1H).

3-(bromomethyl)-4-chlorobenzonitrile

To a stirred solution of 4-chloro-3-(hydroxymethyl)benzonitrile (4.86 g,29.0 mmol) in DCM (100 mL) at room temperature, PBr₃ (3.35 mL, 35.3mmol) was added in portions and stirring continued for 1 hr. Thereaction mixture was quenched with slow additions of saturated NaHCO₃until the aqueous phase was neutral. The organic phase obtained by phaseseparation was washed with water (100 mL), dried over Na₂SO₄, filteredand the filtrate concentrated in vacuo to afford the title compound asan off white solid (3.36 g, 50%) of an off-white solid; ¹H NMR (500 MHz,CDCl₃) δ 4.56 (s, 2H), 7.52 (d, 1H), 7.54 (d, 1H), 7.75 (d, 1H).

3-[(acetylsulfanyl)methyl]-4-chlorobenzonitrile

To a stirring solution of 3-(bromomethyl)-4-chlorobenzonitrile (3.36 g,14.6 mmol) in acetone (30 mL) was added potassium thioacetate (2.0 g,17.5 mmol) and the mixture was left under stirring at room temperaturefor 1 hr. The orange reaction mixture was concentrated in vacuo beforeit was diluted in DCM (130 mL) and washed with water (100 mL). Theorganic phase obtained was dried over Na₂SO₄, filtered and concentratedin vacuo to afford the title compound as an orange solid 2.79 g, 85%);¹H NMR (500 MHz, DMSO) δ 2.36 (s, 3H), 4.22 (s, 2H), 7.71 (d, 1H), 7.79(d, 1H), 7.94 (d, 1H).

(2-chloro-5-cyanophenyl)methanesulfonyl chloride

A stirring suspension of 3-[(acetylsulfanyl)methyl]-4-chlorobenzonitrile(500 mg, 2.22 mmol) in AcOH:water (30:3 mL) at room temperature wassaturated with chlorine gas three times and left stirring for 30 mins.The reaction mixture was degassed with N₂ (to remove excess chlorine),diluted with EtOAc (60 mL), washed with water (2×40 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to afford the title compoundas a yellow oil (358 mg, 65%); ¹H NMR (500 MHz, DMSO) δ 3.94 (s, 2H),7.62 (d, 1H), 7.71 (dd, 1H), 7.92 (d, 1H).

N-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methane-sulfonamide

To a stirring solution of 6-chloro-4-methoxypyridazin-3-amine (319 mg,2.00 mmol) in pyridine (5 mL) at room temperature under N₂ was added(2-chloro-5-cyanophenyl)-methanesulfonyl chloride (500 mg, 2.00 mmol)and the mixture stirred 30 mins. The reaction mixture was concentratedin vacuo to afford viscous orange oil which was diluted in EtOAc (100mL) and washed with water (2×80 mL). The aqueous layers were combinedand more product was extracted with EtOAc (3×100 mL). The organic layerswere combined, dried over Na₂SO₄ and concentrated in vacuo to afford thetitle compound as an orange solid (649 mg, 42%); m/z=372.8, 374.8 (MH)⁺.

6-chloro-4-methoxypyridin-3-amine

To a suspension of 2-chloro-4-methoxy-5-nitropyridine (300 mg, 1.59mmol), prepared according to a literature procedure (PCT Int. Appl.(2003), WO 2003080610 A1 20031002) in EtOH (3 mL) was added SnCl₂.2H₂O(1.44 g, 6.36 mmol) and the the mixture heated at 90° C. for 1 hr. Thesolvents were evaporated and the residue partitioned between 3M NaOH (50mL) and DCM (100 mL). The phases were separated and the organic phasewas washed with brine (20 mL), dried (Na₂SO₄), the mixture filtered andthe filtrate evaporated to dryness to afford the title compound as ayellow oil (174 mg, 69%); m/z=158.9, 160.8 (MH)⁺.

N-(5-bromo-3-methoxypyrazin-2-yl)-1-(3-chlorophenyl)methanesulfonamide

To a solution of 5-bromo-3-methoxypyrazin-2-amine (500 mg, 2.45 mmol) inpyridine (5 mL) at room temperature was added3-chlorophenyl)methanesulfonyl chloride (552 mg, 2.45 mol) over 5 min.The mixture was stirred 10 mins, the pyridine evaporated, then DCM (60mL) and water (10 mL) was added. The phases were separated and theorganic phase was washed with brine (5 mL), dried (Na₂SO₄), the mixturefiltered and the filtrate evaporated to dryness to afford an orange oilwhich was chromatographed on silica (Heptane: EtOAc 1:1) to afford thetitle compound as a light brown solid (483 mg, 48%); m/z=393.7, 395.7(MH)⁺.

1-(3-chlorophenyl)-N-[5-(ethylsulfanyl)-3-methoxypyrazin-2-yl]methanesulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)-pyridin-2-yl]methanesulfonamidewas used except thatN-(5-bromo-3-methoxypyrazin-2-yl)-1-(3-chlorophenyl)methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-(5-iodo-3-methoxypyridin-2-yl)methanesulfonamideand sodium thioethoxide was substituted for propane-2-thiol (77%);m/z=373.8, 376.9 (MH)⁺.

1-(3-chlorophenyl)-N-[5-(ethanesulfonyl)-3-methoxypyrazin-2-yl]methane-sulfonamide

To a solution of1-(3-chlorophenyl)-N-[5-(ethylsulfanyl)-3-methoxypyrazin-2-yl]-methanesulfonamide(285 mg, 0.732 mmol) in acetone (12 mL) and water (2 mL) was addedOXONE® (1.34 g, 2.20 mmol) and the reaction mixture stirred at roomtemperature overnight. The acetone was evaporated, water added (10 mL)followed by DCM (80 mL). The phases were separated and the organic phasewas washed with brine (5 mL), dried (Na₂SO₄), the mixture filtered andthe filtrate evaporated to dryness to afford a yellow solid (333 mg at81% purity, 91% yield) which could be used without further purification;m/z=406.1, 408.1 (MH)⁺.

6-bromo-3-methoxypyridin-2-amine

To a stirred suspension of 6-bromo-3-methoxy-2-nitropyridine, which canbe prepared by literature methods (e.g. M. Lawson et al, Organic &Biomolecular Chemistry, 11(22), 3664-3673; 2013), (3.90 g, 16.7 mmol) inEtOH:Water 1:1 (100 mL) was added iron powder (4.67 g, 83.7 mmol) andsolid ammonium chloride (4.48 g, 83.7 mmol). The mixture was then heatedat 75° C. for 30 mins and mixture filtered while hot. The black filtercake was washed with more hot ethanol (2×50 mL) and the combinedfiltrates were evaporated to near dryness then slurried with water.Filtration gave a tan solid that containing mostly the title compound(1.67 g, 44%); ¹H NMR (500 MHz, DMSO) δ 3.76 (bs, 3H), 6.16 (bs, 2H),6.62 (bs, 1H), 6.94 (bs, 1H).

6-bromo-5-chloro-3-methoxypyridin-2-amine

To a solution of 6-bromo-3-methoxypyridin-2-amine (1.54 g, 6.83 mmol) inAcOH (10 mL) was added N-chlorosuccinimide (1.00 g, 7.51 mmol) and thebrown mixture stirred overnight. The solvent was evaporated and DCM (20mL) and saturated NaHCO₃ (20 mL) were added. The phases were separatedand the organic phase was washed with brine (3 mL), dried (Na₂SO₄), themixture filtered and the filtrate evaporated to dryness to afford abrown solid which was chromatographed on silica (eluent heptane:EtOAc5:1 then 5:3) to afford mainly the title compound as a yellow solid (570mg, 35%) m/z=238.8 (MH)⁺.

N-(6-bromo-5-chloro-3-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-(5-iodo-3-methoxypyridin-2-yl)-methanesulfonamidewas used, except that 6-bromo-5-chloro-3-methoxypyridin-2-amine wassubstituted for 5-iodo-3-methoxypyridin-2-amine (34%); m/z=460.7 (MH)⁺.

5-chloro-3-(hydroxymethyl)benzonitrile

The procedure to prepare 4-chloro-3-(hydroxymethyl)benzonitrile was usedexcept that 5-chloro-3-formylbenzonitrile was substituted for4-chloro-3-formylbenzonitrile (62%); ¹H NMR (500 MHz, CDCl₃) δ 4.77 (s,2H), 7.55-7.61 (m, 2H), 7.63 (d, 1H).

3-[(acetylsulfanyl)methyl]-5-chlorobenzonitrile

To a solution of 5-chloro-3-(hydroxymethyl)benzonitrile (1.25 g, 7.48mmol) in DCM (100 mL) was added neat PBr₃ (2.43 g, 7.48 mmol) and themixture stirred 1 hr. The mixture was quenched by the addition ofsaturated NaHCO₃ until the aqueous phase was neutral or slightly basic.The phases were separated and the organic phase was washed with brine(20 mL), dried (Na₂SO₄), the mixture filtered and the filtrateevaporated to dryness to afford the intermediate bromide as a colourlessoil. This was dissolved in acetone (100 mL), thioacetic acid (569 mg,7.48 mmol) and K₂CO₃ (1.55 g, 11.2 mmol) added and the mixture stirred 1hr. DCM (100 mL) and saturated brine (30 mL) were then added. The phaseswere separated and the organic phase was washed with more brine (10 mL),dried (Na₂SO₄), the mixture filtered and the filtrate evaporated todryness to afford a brown oil, containing the desired title compound(880 mg, 44%); ¹H NMR (500 MHz, CDCl₃) δ 2.41 (s, 3H), 4.09 (s, 2H),7.47-7.59 (m, 3H).

(3-chloro-5-cyanophenyl)methanesulfonyl chloride

The procedure to prepare (2-chloro-5-cyanophenyl)methanesulfonylchloride was used except that3-[(acetylsulfanyl)methyl]-5-chlorobenzonitrile was substituted for3-[(acetyl-sulfanyl)methyl]-4-chlorobenzonitrile (54%); ¹H NMR (500 MHz,CDCl₃) δ 4.87 (s, 2H), 7.71 (s, 1H), 7.76 (s, 1H), 7.80 (s, 1H).

1-(2-chlorophenyl)-N-(6-iodo-4-methoxypyridazin-3-yl)methanesulfonamide

To a solution of 6-iodo-4-methoxypyridazin-3-amine (614 mg, 2.34 mmol)in pyridine (3 mL) at 80° C. was added (2-chlorophenyl)methanesulfonylchloride (500 mg, 2.21 mmol) over 5 min. The mixture was stirred 10 min,the pyridine evaporated and the residue chromatographed on silica(eluent: EtOAc:Heptane 2:1) to afford the title compound as a lightbrown solid (180 mg, 15%); m/x 439.7 (MH)⁺. Note: starting material andproduct also contained the bromo pyridazine (see above).

1-(2-chlorophenyl)-N-[4-methoxy-6-(methylsulfanyl)pyridazin-3-yl]methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)-pyridin-2-yl]methanesulfonamidewas used except that1-(2-chlorophenyl)-N-(6-iodo-4-methoxypyridazin-3-yl)methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-(5-iodo-3-methoxypyridin-2-yl)methanesulfonamideand sodium thiomethoxide was substituted for propane-2-thiol (25%);m/z=359.8, 361.9 (MH)⁺.

1-(2-chlorophenyl)-N-(6-methanesulfonyl-4-methoxypyridazin-3-yl)methane-sulfonamide

The procedure to prepare1-(3-chlorophenyl)-N-[5-(ethanesulfonyl)-3-methoxypyrazin-2-yl]methanesulfonamidewas used except that1-(2-chlorophenyl)-N-[4-methoxy-6-methylsulfanyl)pyridazin-3-yl]methanesulfonamidewas substituted for1-(3-chloro-phenyl)-N-[5-(ethanesulfonyl)-3-methoxypyrazin-2-yl]methanesulfonamide(57%); m/z=391.9, 393.8 (MH)⁺.

Methyl 3-[(5-chloro-4-hydroxypyridin-3-yl)sulfamoyl]benzoate

To a stirred solution of 3-amino-5-chloropyridin-4-ol (500 mg, 3.46mmol) in pyridine (3 mL) was added DMAP (10 mg, 0.08 mmol) and methyl3-(chlorosulfonyl)benzoate (812 mg, 3.46 mmol). The reaction was stirredat 40° C. under nitrogen for 4 hrs. The reaction mixture wasconcentrated in vacuo, diluted in EtOAc (140 mL), the organic layerwashed with water (2×100 mL) and washed with brine. The organic layerwas dried over Na₂SO₄ and concentrated in vacuo to afford the titlecompound as an orange solid (185 mg, 14%); m/z=342.8, 344.9 (MH)⁺.

3-[(5-chloro-4-hydroxypyridin-3-yl)sulfamoyl]benzoic acid

To a stirred solution of methyl3-[(5-chloro-4-hydroxypyridin-3-yl)sulfamoyl]benzoate, 203 mg, 0.59mmol) in ethanol (10 mL) at room temperature was added aqueous sodiumhydroxide (2 M, 1.5 mL) and the reaction stirred at 40° C. undernitrogen for 1 hr. The reaction mixture was concentrated in vacuo beforebeing acidified with 2 M HCl until a pH of 1 was achieved. Theprecipitated solid was collected by vacuum filtration to afford thetitle compound as an orange solid (108 mg, 57%); m/z=328.8 (MH)⁺.

1-(3,4-difluorophenyl)-N-(6-iodo-4-methoxypyridazin-3-yl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that (3,4-difluorophenyl)methane-sulfonyl chloride wassubstituted for (2-chloro-5-cyanophenyl) methanesulfonyl chloride and6-iodo-4-methoxypyridazin-3-amine was substituted for6-chloro-4-methoxypyridazin-3-amine; (57%); ¹H NMR (500 MHz, DMSO) δ3.92 (d, 3H), 4.88 (br.s, 2H), 7.19 (s, 1H), 7.44 (qd, 2H), 7.50-7.68(m, 1H), 10.55 (br.s, 1H).

1-(3,4-difluorophenyl)-N-[4-methoxy-6-(methylsulfanyl)pyridazin-3-yl]methane-sulfonamide

1-(3,4-difluorophenyl)-N-(6-iodo-4-methoxypyridazin-3-yl)methanesulfonamide(680 mg, 1.43 mmol), sodium methanethiolate (121 mg, 1.72 mmol)(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one—palladium (3:2) (65 mg, 0.07mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (85 mg,0.14 mmol) and anhydrous dioxane (12 mL) were charged to a round bottomflask, DIPEA (498 μL, 2.87 mmol) was added and the mixture was degassedby bubbling with nitrogen for approximately 5 min. The mixture wassealed under nitrogen and stirred at 75° C. for 1 h. EtOAc (70 mL) andwater (20 mL) were added and the phases were separated. The aqueous wasback extracted with EtOAc (2×10 mL). The combined organic phases werewashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated in vacuo. The residue obtained was purified byflash column chromatography over silica (Biotage 25 g SNAP cartridge)eluted with heptane:EtOAc 1:0 to 6:4 to 2:8 to afford the title compound(518 mg, 99%) as an off white solid. ¹H NMR (500 MHz, CDCl₃) δ 2.50 (s,3H), 3.93 (s, 3H), 4.44 (s, 2H), 6.47 (s, 1H), 7.10 (dt, 1H), 7.14-7.20(m, 1H), 7.29 (ddd, 1H).

1-(3,4-difluorophenyl)-N-(6-methanesulfonyl-4-methoxypyridazin-3-yl)methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)-pyridin-2-yl]methanesulfonamidewas used except that1-(3,4-difluorophenyl)-N-[4-methoxy-6-(methylsulfanyl)pyridazin-3-yl]methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)pyridin-2-yl]methane-sulfonamideand the pH of the solution was brought to 1 with 1M HCl prior toextraction; (44%)¹H NMR (500 MHz, CDCl₃) δ 3.36 (s, 3H), 4.06 (s, 3H),4.81 (d, 2H), 7.10-7.19 (m, 2H), 7.27-7.31 (m, 1H), 7.37 (s, 1H).

N-(5-bromo-3-methoxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To a stirring solution of 5-bromo-3-methoxypyrazin-2-amine (1.50 g, 7.35mmol) in pyridine (15 mL), DMAP (15 mg, 0.12 mmol) and(3,5-dichlorophenyl)methanesulfonyl chloride (1.91 g, 7.34 mmol) wasadded. The reaction was left stirring at room temperature under nitrogenfor 2 hrs.

A further addition of (3,5-dichlorophenyl)methanesulfonyl chloride (0.20g, 0.77 mmol) was added to the reaction mixture which was then leftstirring for 1 hr at room temperature. The reaction mixture wasconcentrated in vacuo resulting in a viscous orange mixture which wasthen diluted with EtOAc (100 mL), washed with water (2×80 mL), theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to affordan orange solid. This was dissolved in EtOAc (30 mL) and acidified withHCl (2M, 20 mL) which resulted in the precipitation of the titlecompound as a white solid. The organic and aqueous layer weresubsequently separated, the organic layer was washed with water (3×30mL), dried over Na₂SO₄ and concentrated in vacuo to afford a second cropof the title compound as an orange solid (combined yield 1.73 g, 54%);¹H NMR (500 MHz, DMSO) δ 3.93 (s, 3H), 4.88 (s, 2H), 7.36 (d, 2H), 7.63(m, 1H), 8.12 (s, 1H), 10.80 (s, 1H).

N-(5-cyano-3-methoxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To a solution ofN-(5-bromo-3-methoxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methane-sulfonamide(250 mg, 0.585 mol) in NMP (10 mL) was added solid copper(I) cyanide(262 mg, 2.93 mmol) and the mixture heated at 170° C. for 1 hr. Thecooled reaction mixture was then treated with EtOAc (50 mL) and diluteammonia (15 mL). The phases were separated and the organic phase waswashed with brine (5 mL), dried (Na₂SO₄), the mixture filtered and thefiltrate evaporated to dryness to afford a brown oil containing NMP anddesired product. Carried over into next step without furtherpurification; m/z=372.8, 374.9 (MH)⁺.

1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propylsulfanyl)pyridazin-3-yl]methane-sulfonamide

A stirred solution ofN-(6-chloro-4-methoxypyridazin-3-yl)-1-(3,5-dichlorophenyl)-methanesulfonamide(800 mg, 2.09 mmol), propane-1-thiol (159 mg, 2.09 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (121 mg, 0.21mmol) in 1,4-Dioxane (18 mL) was degassed for 15 min, then followeddropwise addition of DIPEA (540 mg, 4.18 mmol) then(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one—palladium (3:2) (72 mg, 0.08mmol). The mixture was degassed for a further 5 mins then stirred at at90° C. for a 3.5 hrs. The cooled mixture was filtered, the filtrate wasconcentrated and the residue dissolved in EtOAc, and the resultant layerwashed with water and brine. The organic layer was concentrated and theresidues purified by flash silica chromatography (eluent 25% EtOAc inhexane) to afford the title compound as a yellow solid (450 mg, 51%); ¹HNMR (400 MHz, DMSO) δ 0.98 (t, 3H), 1.68 (m, 2H), 3.14 (t, 2H), 3.88 (s,3H), 4.68 (s, 2H), 7.09 (s, 1H), 7.41 (m, 2H), 7.57 (s, 1H).

1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propane-1-sulfonyl)pyridazin-3-yl]-methanesulfonamide

The method used to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)pyridin-2-yl]methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propylsulfanyl)pyridazin-3-yl]methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)pyridin-2-yl]methane-sulfonamide(51%); ¹H NMR (400 MHz, DMSO) δ 0.97 (t, 3H), 1.68 (m, 2H), 3.49-3.62(m, 2H), 4.03 (s, 3H), 4.97 (s, 2H), 7.41 (s, 2H), 7.62 (s, 2H), 11.21(s, 1H).

5-chloro-2-nitropyridin-3-ol

5-chloropyridin-3-ol (2.00 g, 15.4 mmol) was dissolved in concentratedH₂SO₄ (15 mL) at 5° C. Concentrated nitric acid (1.0 mL) was then added.The reaction was allowed to warm to room temperature over 3 hrs. Thereaction solution was poured onto ice water (25 mL). The resultantprecipitate was filtered, washed with water and dried overnight at 40°C. in vacuo to afford was obtained as a yellow powder, (1.80 g, 67%); ¹HNMR (400 MHz, CDCl₃) δ 7.68 (d, 1H), 8.15 (d, 1H), 10.29 (s, 1H).

5-chloro-2-nitro-3-(prop-2-en-1-yloxy)pyridine

To a solution of 5-chloro-2-nitropyridin-3-ol (1.5 g, 8.59 mmol) inacetonitrile (30 mL) was added K₂CO₃ (2.38 g, 17.2 mmol) and the mixturestirred for 15 mins followed by dropwise addition of 3-bromoprop-1-ene(1.25 g, 10.31 mmol). The reaction mixture was refluxed for 16 hrs,cooled and filtered. The filtrate was concentrated and the residuepurified by flash silica chromatography (eluent 1:9 EtOAc) to afford thetitle compound as a yellow solid (1.40 g, 76%); ¹H NMR (400 MHz, CDCl₃)δ 4.72 (dt, 2H), 5.45 (m, 2H), 6.01 (m, 1H), 7.50 (d, 1H), 8.04 (d, 1H).

5-chloro-3-(prop-2-en-1-yloxy)pyridin-2-amine

To a stirred solution of 5-chloro-2-nitro-3-(prop-2-en-1-yloxy)pyridine(1.40 g, 6.52 mmol) in ethanol (150 mL) was added iron powder (3.64 g,65.2 mmol) and 1 mL of conc. HCl at room temperature for 1 hr. Thecooled mixture was filtered through Celite and the filtrate concentratedto dryness. 1M NaOH was added to make the mixture basic and this wasthen extracted with EtOAc. The organic layer was dried (MgSO₄), filteredand the filtrate concentrated to obtain the title compound as a brownsolid (0.800 g, 66%); ¹H NMR (400 MHz, CDCl₃) δ 4.55 (d, 2H), 4.72 (s,2H), 5.49-5.26 (m, 2H), 6.03 (ddd, 1H), 6.89 (d, 1H), 7.64 (d, J=1.7 Hz,1H).

N-[5-chloro-3-(prop-2-en-1-yloxy)pyridin-2-yl]-1-(3,5-dimethoxyphenyl)methane-sulfonamide

To 1-(bromomethyl)-3,5-dimethoxybenzene (1.00 g, 4.33 mmol) in acetone(18 mL) was added disodium sulfite (0.55 g, 4.33 mmol) in water (5 mL)and the mixture refluxed. After completion of the reaction, as judged bydisappearance of starting material on TLC, the mixture was cooled toroom temperature and concentrated. The resulting white precipitate wasfiltered off and the solid washed with DCM (30 mL) then dried under highvacuum to give the sodium (3,5-dimethoxyphenyl)methanesulfonate (780 mg,71%)

A stirred solution of sodium (3,5-dimethoxyphenyl)methanesulfonate (800mg, 3.15 mmol) in DCM (25 mL) and a few drops of DMF was cooled to −20°C. then oxalyl chloride (26901, 31.4 mmol) was added The mixture wasstirred for 30 min at this temperature then allowed to warm to roomtemperature and stirred for 2 hrs. DCM was added and organic phasewashed with water and brine (2×40 mL). The organic layer was dried(Na₂SO₄) and concentrated to obtain of(3,5-dimethoxyphenyl)methanesulfonyl chloride as a yellow liquid whichwas used immediately (678 mg).

To a stirred solution of 5-chloro-3-(prop-2-en-1-yloxy)pyridin-2-amine(500 mg, 2.71 mmol) in DCM (15 mL), was added DIPEA (1050 mg, 8.12mmol). After 10-15 mins (3,5-dimethoxyphenyl)methanesulfonyl chloride(678 mg, 2.71 mmol) was added and the reaction mixture stirred at roomtemperature for 16 hrs. It was then concentrated and the residuesuspended in water and extracted with EtOAc (3×50 mL). The organic layerwas dried (Na₂SO₄), filtered and the filtrate concentrated. The residuewas purified by automated reverse-phase HPLC (low pH method) to affordthe title (35 mg, 3%) as an off white solid; m/z=399 (MH)⁺.

5,6-dichloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide

5-chloro-3-methoxypyridin-2-amine (250 mg, 1.58 mmol) was dissolved inpyridine (2 mL). The solution was cooled to 0-5° C. To this coldsolution 5,6-dichloropyridine-3-sulfonyl chloride (389 mg, 1.58 mmol)was added and the resultant reaction mixture was stirred at roomtemperature overnight. To this reaction mixture water was added and itwas extracted with DCM. The combined organic layer was dried over Na₂SO₄and evaporated under reduced pressure. The residue was purified usingflash silica chromatography (20% EtOAc in hexane) to afford the titlecompound as an off white solid (70 mg, 11%); m/z=368.3, 370.3 (MH)⁺.

5-chloro-N-(5-chloro-3-methoxypyridin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide

A solution of5,6-dichloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide(150 mg, 0.41 mmol) and 40% aqueous dimethylamine (50 mg, 0.45 mmol) inTHF (5 mL) was mixed in a sealable tube. The tube was sealed and heated12 hrs at 90° C. To this reaction mixture water (3 mL) was added and itwas extracted with DCM (3×5 mL). The combined organic layers were driedover Na₂SO₄ and evaporated under reduced pressure to afford the titlecompound as an off white solid (145 mg, 95%); ¹H NMR (400 MHz, CDCl₃) δ3.18 (s, 6H), 3.86 (s, 3H), 7.03 (d, 1H), 7.84 (m, 1H), 8.17 (d, 1H),8.73 (d, 1H).

2-chloro-4-methoxypyrimidin-5-amine

5.4M sodium methoxide (100 μL, 0.54 mmol) was added dropwise to astirring solution of 2,4-dichloropyrimidin-5-amine (89 mg, 0.54 mmol) inmethanol (2 mL) at 0° C. under nitrogen. The reaction was allowed towarm to room temperature and stirred for 1 hr. The reaction was treatedwith more 5.4M sodium methoxide (10 μL) and stirred for a further 1 hr,then left to stand at room temperature for 64 hrs. The reaction wasquenched with acetic acid (1 mL) and concentrated in vacuo. The residuewas dissolved in EtOAc (20 mL) and washed with saturated aqueous NaHCO₃(2×6 mL), brine (6 mL), dried over Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo. The residue obtained was purified by flash columnchromatography over silica (Biotage 10 g SNAP cartridge) eluting withheptane:EtOAc, smooth gradient 1:0 to 7:3 to afford the title compoundas a white solid (80 mg, 83%); ¹H NMR (500 MHz, DMSO) δ 3.93 (s, 3H),5.31 (s, 2H), 7.72 (s, 1H).

N-(2-chloro-4-methoxypyrimidin-5-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

(3,5-dichlorophenyl)methanesulfonyl chloride (128 mg, 0.49 mmol) wasadded to a solution of 2-chloro-4-methoxypyrimidin-5-amine (75 mg, 0.47mmol) and DIPEA (123 μL, 0.71 mmol) in DCM (2 mL). The reaction wasallowed to stir at room temperature for 18 hrs. The reaction was treatedwith more (3,5-dichlorophenyl)methanesulfonyl chloride (20 mg, 0.08mmol) and stirred for a further 4 hrs. The reaction was diluted with DCM(15 mL), washed with saturated aqueous citric acid (2×6 mL), sat. aq.NaHCO₃ (2×6 mL), brine (6 mL), dried over anhydrous sodium sulfate,filtered and the filtrate was concentrated in vacuo. The residueobtained was purified by flash column chromatography over silica(Biotage 10 g SNAP cartridge) eluting with Heptane:EtOAc constantgradient 1:0 to 7:3 to afford the title compound (108 mg, 60%) as awhite solid; m/z=381.8, 383.9 (MH)⁺.

1-(3,5-dichlorophenyl)-N-[5-(ethanesulfanyl)-3-methoxypyridin-2-yl]methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-yl-sulfanyl)pyridin-2-yl]methanesulfonamidewas used except that ethanethiol was substituted for propane-2-thiol(59%); m/z=407.3, 405.3 (MH)⁺.

1-(3,5-dichlorophenyl)-N-[5-(ethanesulfonyl)-3-methoxypyridin-2-yl]methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)-pyridin-2-yl]methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-[5-(ethanesulfanyl)-3-methoxypyridin-2-yl]methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)pyridin-2-yl]methanesulfonamide(70%); m/z=439.4, 441.4 (MH)⁺.

1-(3,5-dichlorophenyl)-N-[6-(ethylsulfanyl)-4-methoxypyridazin-3-yl]methane-sulfonamide

The procedure for the preparation of1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propyl-sulfanyl)pyridazin-3-yl]methanesulfonamidewas used except that ethanethiol was substituted for propane-1-thiol.Purification was carried out after workup using ether/pentanerecrystallisation (65%); ¹H NMR (400 MHz, CDCl₃), δ 1.34 (t, 3H),3.01-3.04 (m, 2H), 3.94 (s, 3H), 4.34 (s, 2H), 6.40 (s, 1H), 7.25-7.29(m, 1H), 7.34 (d, 2H).2

1-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-4-methoxypyridazin-3-yl]methanesulfonamide

The procedure for the preparation of1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)pyridin-2-yl]methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-[6-(ethylsulfanyl)-4-methoxypyridazin-3-yl]methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)pyridin-2-yl]methane-sulfonamide(51%); ¹H NMR (400 MHz, DMSO), δ 1.21 (t, 3H), 3.57-3.62 (m, 2H), 4.03(s, 3H), 4.97 (s, 2H), 7.41 (s, 2H), 7.63 (s, 2H).

1-(3,5-dichlorophenyl)-N-(5-methanesulfanyl-3-methoxypyrazin-2-yl)methane-sulfonamide

The procedure for preparation of1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propyl-sulfanyl)pyridazin-3-yl]methanesulfonamidewas used except thatN-(5-bromo-3-methoxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamideand sodium methanethiolate was substituted for propane-1-thiol; (94%);m/z=393.8, 395.9 (MH)⁺.

1-(3,5-dichlorophenyl)-N-(5-methanesulfonyl-3-methoxypyrazin-2-yl)methane-sulfonamide

To a solution of1-(3,5-dichlorophenyl)-N-(5-methanesulfanyl-3-methoxypyrazin-2-yl)methanesulfonamide(418 mg, 1.06 mmol) in DCM (15 mL) was added mCPBA (522 mg, 70%, 2.12mmol) and the reaction stirred at room temperature for 3 hrs. More mCPBAwas added every hour (200 mg each time) until all the sulfoxideintermediate had converted to sulfone, as judgded by LCMS. The solventwas evaporated and the solid chromatographed on silica (eluent:heptane:EtOAc 3:1 then 1:1 then neat EtOAc) to afford the title compoundas a colourless oil (213 mg, 47%); m/z=425.8, 427.9 (MH)⁺.

2,5-dichloro-N-(6-chloro-4-methoxypyridazin-3-yl)thiophene-3-sulfonamide

A mixture of 6-chloro-4-methoxypyridazin-3-amine (200 mg, 1.25 mmol) and2,5-dichlorothiophene-3-sulfonyl chloride (347 mg, 1.38 mmol) wasdissolved in DCM (5 mL). To that solution pyridine (991 mg, 13 mmol) wasadded and reaction mixture was stirred at room temperature for 12 h.Water was added and the mixture was extracted with EtOAc (3×30 mL). Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand the filtrate evaporated to give the crude title compound as an offwhite solid which was used without further purification (180 mg at 51%,19%); m/z=374.1, 376.1 (MH)⁺.

5-bromo-6-chloro-N-(6-chloro-4-methoxypyridazin-3-yl)pyridine-3-sulfonamide

To a suspension of 6-chloro-4-methoxypyridazin-3-amine (3.00 g, 18.8mmol) in dry dimethoxyethane (60 mL) was added sodium hydride (752 mg,60%, 18.8 mmol) and the mixture stirred 5 mins.5-bromo-6-chloropyridine-3-sulfonyl chloride (4.92 g, 16.9 mmol) wasthen added and the mixture stirred 1 hr. EtOAc was added (100 mL)followed by water (15 mL) and the phases were separated. The aqueousphase was then acidified (1M HCl) resulting in a white emulsion. MoreEtOAc (50 mL) was added. The phases were separated and the organic phasewas washed with brine (15 mL), dried (Na₂SO₄), the mixture filtered andthe filtrate evaporated to dryness to afford an off white solidcontaining the title compound (1.03 g, 13%); m/z=412.7, 414.7 (MH)⁺.

N-(6-chloro-4-methoxypyridazin-3-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide

Excess NaH (301 mg, low purity) was added to a stirred solution of6-chloro-4-methoxy-pyridazin-3-amine (200 mg, 1.26 mmol) in DME (6 mL)under nitrogen at room temperature. After 1 hr3-(trifluoromethoxy)benzene-1-sulfonyl chloride (359 mg, 1.38 mmol) wasadded and the resultant mixture was stirred for 2 hrs at roomtemperature. Aqueous citric acid was added and the aqueous phase wasextracted with EtOAc (3×30 mL). The combined organic layers were driedon Na₂SO₄ filtered and the filtrate evaporated to afford the crude titlecompound as a brown solid (210 mg at 81% purity, 35%); m/z=384.2, 386.2(MH)⁺.

1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propan-2-ylsulfanyl)pyridazin-3-yl]-methanesulfonamide

The method to prepare1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propylsulfanyl)-pyridazin-3-yl]methanesulfonamidewas used except that propan-2-thiol was substituted for propan-1-thiol(51%); m/z=422.4, 424.4 (MH)⁺.

1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propane-2-sulfonyl)pyridazin-3-yl]-methanesulfonamide

The method to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)-pyridin-2-yl]methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propan-2-ylsulfanyl)pyridazin-3-yl]methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfanyl)pyridin-2-yl]methane-sulfonamide(52%); m/z=454.4, 456.4 (MH)⁺.

5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide

The procedure to prepare5-chloro-N-(5-chloro-3-methoxypyridin-2-yl)-6-(dimethyl-amino)pyridine-3-sulfonamidewas used except that5-bromo-6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamidewas substituted for5,6-dichloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide(81%);%); m/z=421.3, 423.3 (MH)⁺.

N-(6-chloro-4-methoxypyridazin-3-yl)-3-cyanobenzene-1-sulfonamide

To a suspension of potassium 2-methylpropan-2-olate (70 mg, 0.63 mmol)in THF (4 mL) at 0° C. was added 6-chloro-4-methoxypyridazin-3-amine(100 mg, 0.63 mmol) and stirred for 30 mins. 3-cyanobenzene-1-sulfonylchloride (126 mg, 0.63 mmol) was added to the reaction mixture and wasstirred for 18 hrs at room temperature. The reaction mixture was dilutedwith EtOAc (15 mL) and washed with 1M aqueous HCl (10 mL). The organicphase was dried using Na₂SO₄, filtered and concentrated. The cruderesidue was purified using silica column chromatography (DCM:MeOH 90:10)to yield the title compound (63 mg, 30%); m/z=323.0, 325.0 (MH)⁺.

1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propylsulfanyl)pyridin-2-yl]methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)-pyridin-2-yl]methanesulfonamidewas used except that propane-1-thiol was substituted for propane-2-thiol(65%); ¹H NMR (400 MHz, DMSO) δ 0.97 (t, 3H), 1.58 (m, 2H), 2.97 (t,2H), 3.81 (s, 3H), 4.90 (s, 2H), 7.34 (d, 2H), 7.41 (d, 1H), 7.61 (s,1H), 7.91 (d, 1H), 9.97 (s, 1H).

1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-1-sulfonyl)pyridin-2-yl]methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)-pyridin-2-yl]methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propylsulfanyl)pyridin-2-yl]methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)pyridin-2-yl]methanesulfonamide(61%); m/z=453.0, 455.0 (MH)⁺.

1-(3,5-dichlorophenyl)-N-(6-methanesulfanyl-4-methoxypyridazin-3-yl)methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propylsulfanyl)-pyridazin-3-yl]methanesulfonamidewas used except that sodium methanethiolate was substituted forpropane-1-thiol (56%); ¹H NMR (400 MHz, CDCl₃) δ 2.45 (s, 3H), 3.95 (s,3H), 4.31 (s, 2H), 6.42 (s, 1H), 7.26-7.39 (m, 3H).

1-(3,5-dichlorophenyl)-N-(6-methanesulfonyl-4-methoxypyridazin-3-yl)methane-sulfonamide

To a solution of1-(3,5-dichlorophenyl)-N-(6-methanesulfanyl-4-methoxypyridazin-3-yl)methanesulfonamide(800 mg, 2.03 mmol) in chloroform (25 mL) was added mCPBA (1.05 g, 6.09mmol) and the reaction mixture stirred for 16 hrs at room temperature.The chloroform was evaporated and the crude residue purified directly bysilica chromatography (eluent DCM:MeOH (95:5) to afford the titlecompound (500 mg at 64% purity, 37%) as a white solid. ¹H NMR (400 MHz,DMSO) δ 3.39 (s, 3H), 3.97 (s, 3H), 4.82 (s, 2H), 7.39 (s, 1H), 7.59 (s,1H), 7.72 (s, 1H), 7.91 (s, 2H).

4-(bromomethyl)thiophene-2-carbonitrile

4-methylthiophene-2-carbonitrile (900 mg, 7.31 mmol) was dissolved incarbon tetrachloride (20 mL) then N-bromosuccinimide (1.43 g, 8.03 mmol)and AIBN (120 mg, 0.73 mmol) were added and the resulting reactionmixture was refluxed for 8 hrs. To the cooled reaction mixture was addedwater and the product was extracted with EtOAc (3×10 mL). The combinedorganic layers were dried on Na₂SO₄, the mixture filtered and thesolvent evaporated. The residue was purified by silica chromatography(eluent: 2% EtOAc in n-hexane) to afford the title compound as a whitesolid (810 mg, 49%); (400 MHz, CDCl₃) δ 4.44 (s, 2H), 7.53 (m, 1H),7.61-7.67 (m, 1H).

4-[(acetylsulfanyl)methyl]thiophene-2-carbonitrile

4-(bromomethyl)thiophene-2-carbonitrile (800 mg, 3.96 mmol) wasdissolved in acetone then potassium thioacetate (1.13 g, 9.91 mmol) wasadded and the reaction mixture stirred at room temperature for 2 hrs.Water was added to the reaction mixture and the compound was extractedwith EtOAc (3×30 mL). The combined organic layers were dried on Na₂SO₄,the solvents evaporated. The crude residue was purified by silicachromatography (eluent 2% EtOAc in n-hexane) to afford the titlecompound as a brown oil (710 mg, 86%); (400 MHz, CDCl₃) δ 2.37 (s, 3H),4.07 (s, 2H), 7.42 (s, 1H), 7.52 (s, 1H).

N-(5-chloro-3-methoxypyridin-2-yl)-1-(5-cyanothiophen-3-yl)methanesulfonamide

A solution of 4-[(acetylsulfanyl)methyl]thiophene-2-carbonitrile (400mg, 2.03 mmol) in a mixture of acetic acid (16 mL) and water (4 mL) wastreated with gaseous chlorine and stirred until the colour changed frombrown to pale yellow. Excess chlorine was removed by passing a stream ofN₂ gas through the solution. The reaction mixture was diluted with EtOAcand brine. The phases were separated and the organic phase was washedwith brine, dried on Na₂SO₄ and evaporated to afford the intermediatesulfonyl chloride which was dissolved in DCM then5-chloro-3-methoxypyridin-2-amine (354 mg, 2.22 mmol) was added to itfollowed by pyridine (3 mL). The reaction mixture was then stirred atroom temperature for 12 hrs. The solvents were evaporated and theresidue purified by preparative TLC (eluent 2% MeOH in DCM) twice toafford the title compound (190 mg, 26%) as an off white solid;m/z=343.0, 345.0 (MH)⁺.

5-amino-2-(trifluoromethyl)pyridin-4-ol

To a stirred solution of 5-nitro-2-(trifluoromethyl)pyridin-4-ol, madeby a literature method (U.S. Pat. No. 7,767,687, 2010) (720 mg, 3.46mmol) in MeOH (5 mL) at room temperature was added ammonium chloride(925 mg, 17.3 mmol) in water (25 mL). Iron powder (966 mg, 17.3 mmol)was then added to the stirred suspension and the reaction heated at 80°C. overnight. The solvent was removed and the residual crude solidsonicated sequentially with dichloromethane (20 mL) then 1:1CHCl₃/propan-2-ol (30 mL). The combined solutions were evaporated togive the title compound as a brown solid (528 mg, 85%); ¹H NMR (500 MHz,DMSO-d6) δ 5.31 (s, 2H), 6.99 (s, 1H), 7.88 (s, 1H), 10.81 (s, 1H).

N-(5-chloro-6-cyano-3-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)methane-sulfonamide

A solution ofN-(6-bromo-5-chloro-3-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)-methanesulfonamide(220 mg at 70% purity, 0.334 mmol) in NMP (1 mL) was treated with solidCuCN (150 mg, 1.67 mmol) and the mixture stirred at 165° C. for 2 hrs.The cooled reaction mixture was then partitioned between EtOAc (50 mL)and 0.5M NH₃ (50 mL). The phases were separated and the organic phasewas washed with water (2×5 mL), brine (5 mL), dried (Na₂SO₄), themixture filtered and the filtrate evaporated to dryness to afford abrown oil containing some title compound which was taken onto final stepwithout further purification 135 mg at 36% purity, 66% yield);m/z=405.8, 407.8 (MH)⁺.

N-[5-(cyclopentanesulfanyl)-3-methoxypyridin-2-yl]-1-(3,5-dichlorophenyl)methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)-pyridin-2-yl]methanesulfonamidewas used except that cyclopentanethiol was substituted forpropane-2-thiol (60%); m/z=447.4, 449.4 (MH)⁺.

N-[5-(cyclopentanesulfonyl)-3-methoxypyridin-2-yl]-1-(3,5-dichlorophenyl)methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)pyridin-2-yl]methanesulfonamidewas used except thatN-[5-(cyclopentanesulfanyl)-3-methoxypyridin-2-yl]-1-(3,5-dichlorophenyl)methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)pyridin-2-yl]methanesulfonamide(76%); m/z=479.4, 481.4 (MH)⁺.

N-(5-chloro-6-methanesulfanyl-3-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)-methanesulfonamide

To a stirring solution ofN-(6-bromo-5-chloro-3-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide(1.48 g, 3.20 mmol) in 1,4-dioxane (40 mL), NaSMe (898 mg, 12.8 mmol),(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one—palladium (3:2) (293 mg, 0.32mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (371mg, 0.64 mmol) and DIPEA (1.66 g, 12.8 mmol) were all added to thereaction mixture under stirring at room temperature. The reactionmixture was degassed with N₂ for 2 mins before being left stirring for 2hrs at 80° C. The reaction mixture was retreated with all the reagentsat the same quantities and left stirring for a further 2 hrs at 80° C.Finally, the reaction mixture was retreated with all the reagents athalf the quantities originally used and left under stirring for afurther 2 hrs at 100° C. The reaction mixture was diluted with EtOAc(120 mL) and washed with brine (2×80 mL). The aqueous layers werecombined and extracted with EtOAc (5×120 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo. Thebrown solid residue was purified via column chromatography (eluent15-30% EtOAc in heptane), to afford the title compound as a yellow solid(586 mg, 39%); ¹H NMR (500 MHz, DMSO) δ 2.56 (s, 3H), 3.80 (s, 3H), 4.85(s, 2H), 7.34 (d, 2H), 7.62 (dd, 2H), 10.25 (s, 1H).

N-(5-chloro-6-methanesulfonyl-3-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)-methanesulfonamide

The method to prepare1-(3-chlorophenyl)-N-[5-(ethanesulfonyl)-3-methoxypyrazin-2-yl]methanesulfonamidewas used except thatN-(5-chloro-6-methanesulfanyl-3-methoxy-pyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamidewas substituted for 1-(3-chloro-phenyl)-N-[5-(ethylsulfanyl)-3-methoxypyrazin-2-yl]methanesulfonamide (80%); ¹H NMR (500MHz, DMSO) δ 3.42 (s, 3H), 3.94 (s, 3H), 4.94 (s, 2H), 7.38 (d, 2H),7.63 (m, 1H), 7.78 (s, 1H), 10.80 (s, 1H).

5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide

A solution of5-bromo-6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide(1.40 g, 3.39 mmol) and 40% aqueous dimethylamine (0.573 g, 5.08 mmol)in THF (10 mL) was heated for 12 hrs at 90° C. in a sealed tube. Thecooled mixture was diluted with water (5 mL) and extracted with DCM(3×15 mL). The combined organic fraction was dried over Na₂SO₄ andevaporated under reduced pressure to afford the title compound as an offwhite solid (1.3 g, 86%); ¹H NMR (400 MHz, CDCl₃) δ 3.17 (s, 6H), 3.86(s, 3H), 7.03 (d, 1H), 7.84 (d, 1H), 8.38 (d, 1H), 8.77 (d, 1H).

N-(5-chloro-3-methoxypyridin-2-yl)-6-(dimethylamino)-5-(methylsulfanyl)pyridine-3-sulfonamide

A mixture of5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide(150 mg, 0.356 mmol), sodium methanethiolate (38 mg, 0.534 mmol) andK2CO3 (73 mg, 0.534 mmol) in a mixture of dioxane (3 mL) and water (1mL) was degassed for 15 mins using argon.1,1′-bis(diphenylphosphanyl)ferrocene-dichloropalladium (1:1) (25 mg,0.034 mmol) was added and the reaction mixture was heated in a sealedtube at 90° C. overnight. The cooled reaction mixture was diluted withmore water and EtOAc added. The organic phase was separated and driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified using flash silica chromatography (eluent 35% EtOAcin hexane) to afford the title compound as an off white solid (40 mg,26%); ¹H NMR (400 MHz, CDCl₃) δ 2.47 (s, 3H), 3.09 (s, 6H), 3.86 (s,3H), 7.02 (m, 1H), 7.58 (s, 1H), 7.82 (m, 1H), 8.10 (d, 1H), 8.65 (d,1H).

N-(5-chloro-3-methoxypyridin-2-yl)-6-(dimethylamino)-5-methanesulfonylpyridine-3-sulfonamide

N-(5-chloro-3-methoxypyridin-2-yl)-6-(dimethylamino)-5-(methylsulfanyl)pyridine-3-sulfonamide(60 mg, 0.15 mmol) was dissolved in DCM (3 mL) and mCPBA (143 mg, 77%purity, 0.46 mmol) was added. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated and it wasmade basic using aqueous NaHCO₃. The aqueous layer was extracted withEtOAc (3×15 mL). The combined organic phases were dried (MgSO₄),filtered and the filtrate evaporated to dryness. The residue waspurified using silica column chromatography (eluent 45% EtOAc in hexane)to afford the title compound as an off white solid (60 mg at 29% purity,13%); m/z=421.3, 421.5 (MH)⁺.

1-(3,5-dichlorophenyl)-N-{4-methoxy-6-[(3-methoxypropyl)sulfanyl]pyridazin-3-yl}methanesulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propylsulfanyl)-pyridazin-3-yl]methanesulfonamidewas used except that 3-methoxypropane-1-thiol was substituted forpropane-1-thiol (39%); ¹H NMR (400 MHz, CDCl₃), δ 1.88-1.94 (m, 2H),3.10 (t, 2H), 3.35 (s, 3H), 3.47 (t, 2H), 3.94 (s, 3H), 4.33 (s, 2H),6.42 (s, 1H), 7.26 (s, 1H), 7.34 (s, 2H).

1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(3-methoxypropanesulfonyl)pyridazin-3-yl]methanesulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)-pyridin-2-yl]methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-{4-methoxy-6-[(3-methoxypropyl)sulfanyl]pyridazin-3-yl}methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)pyridin-2-yl]methanesulfonamide(52%); ¹H NMR (400 MHz, DMSO), δ 1.86-1.93 (m, 2H), 3.19 (s, 3H), 3.39(t, 2H), 3.59 (t, 2H), 4.03 (s, 3H), 4.95 (s, 2H), 7.41 (s, 2H), 7.63(s, 2H).

N-[6-(cyclopentylsulfanyl)-4-methoxypyridazin-3-yl]-1-(3,5-dichlorophenyl)-methanesulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propylsulfanyl)pyridazin-3-yl]methanesulfonamidewas used except that cyclopentanethiol was substituted forpropan-1-thiol (59%); m/z=448.4, 450.4 (MH)⁺.

N-[6-(cyclopentanesulfonyl)-4-methoxypyridazin-3-yl]-1-(3,5-dichlorophenyl)-methanesulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)-pyridin-2-yl]methanesulfonamidewas used except thatN-[6-(cyclopentyl-sulfanyl)-4-methoxypyridazin-3-yl]-1-(3,5-dichlorophenyl)methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propan-2-ylsulfanyl)pyridin-2-yl]methane-sulfonamide(65%); ¹H NMR (400 MHz, DMSO-d6), δ 1.63 (m, 4H), 1.93 (dt, 4H), 4.03(s, 3H), 4.13 (d, 1H), 4.94 (s, 2H), 7.40 (s, 2H), 7.62 (d, 2H).

(+/−)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethan-1-ol

2M (Methylsulfanyl)methane—borane (1:1) (3.12 mL, 6.24 mmol) was addedslowly to a stirring solution of1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (1.52 g, 6.24 mmol) inanhydrous THF (18 mL) under nitrogen. The reaction was allowed to stirat room temperature for 1 hr. The reaction was quenched by the carefuladdition of MeOH (5 mL) at 0° C., then concentrated in vacuo and theresidue was purified by flash column chromatography over silica (Biotage25 g SNAP cartridge, eluent: a gradient of heptane:EtOAc 1:0 to 8.5:1.5)to afford the title compound (1.44 g, 88%) as a colourless liquid. ¹HNMR (500 MHz, CDCl₃) δ 4.99 (dt, 1H), 7.34-7.46 (m, 3H).

(+/−)-1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene

N-bromo succinimide (1.99 g, 0.01 mol) was added portionwise at 0° C. toa stirring solution of(+/−)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethan-1-ol (1.44 g, 0.01mol) and triphenyl phosphite (2.93 mL, 0.01 mol) in DCM (15 mL). Thereaction was sealed under nitrogen, allowed to warm to room temperatureand stirred for 18 hrs. The reaction was concentrated in vacuo and theresidue slurried in Et₂O (50 mL), filtered over glass fibre filter paperand the filter pad was washed with Et₂O (4×30 mL). The combinedfiltrates were concentrated in vacuo and the residue was purified byflash column chromatography over silica (Biotage 25 g SNAP cartridge,eluent: gradient of heptane:EtOAc 1:0 to 8.5:1.5) to afford the titlecompound as a pale brown liquid (1.35 g, 79%); ¹H NMR (500 MHz, CDCl₃) δ5.03 (q, 1H), 7.37-7.45 (m, 3H).

(+/−)-1-{[1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl]sulfanyl}ethan-1-one

The procedure to prepare4-[(acetylsulfanyl)methyl]thiophene-2-carbonitrile was used except that(+/−)-1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene wassubstituted for 4-(bromomethyl)thiophene-2-carbonitrile; ¹H NMR (500MHz, CDCl₃) δ 2.43 (s, 3H), 5.15 (q, 1H), 7.27 (d, 2H), 7.37 (t, 1H).

(+/−)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-sulfonyl chloride

The procedure to prepare (2-chloro-5-cyanophenyl)methanesulfonylchloride was used except that(+/−)-1-{[1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl]sulfanyl}-ethan-1-onewas substituted for 3-[(acetylsulfanyl)methyl]-4-chlorobenzonitrile; ¹HNMR (250 MHz, CDCl₃) δ 5.20 (q, 1H), 7.50 (d, 2H), 7.59 (t, 1H).

(+/−)-N-(5-bromo-3-methoxypyrazin-2-yl)-1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethane-1-sulfonamide

(+/−)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-sulfonyl chloride(165 mg, 0.48 mmol) was added to a solution of5-bromo-3-methoxypyrazin-2-amine (107 mg, 0.53 mmol) in anhydrouspyridine (5 mL) The reaction was sealed under nitrogen and stirred atroom temperature for 60 min then at 60° C. for 45 min. The reaction wasallowed to cool to room temperature then concentrated in vacuo. Theresidue was purified over silica (Biotage 10 g SNAP cartridge) elutedwith Heptane:EtOAc 1:0 to 8:2 to 6:4 to 4:6 to afford the title compound(20 mg, 7%) as a light brown solid. ¹H NMR (500 MHz, CDCl₃) δ 4.06 (s,3H), 5.71 (q, 1H), 7.36 (br.s, 1H), 7.46 (d, 2H), 7.49 (m, 1H), 8.03 (s,1H).

Methyl 3-[(5-bromo-3-methoxypyrazin-2-yl)sulfamoyl]benzoate

The procedure to prepareN-(5-bromo-3-methoxypyrazin-2-yl)-1-(3-chlorophenyl)-methanesulfonamidewas used except that methyl 3-(chlorosulfonyl)benzoate was substitutedfor 3-chlorophenyl)methanesulfonyl chloride. In addition, the reactionwas carried out at 60° C. rather than at room temperature (15%);m/z=401.9, 403.9 (MH)⁺.

3-[(5-bromo-3-hydroxypyrazin-2-yl)sulfamoyl]benzoic acid

To a stirred solution of methyl3-[(5-bromo-3-methoxypyrazin-2-yl)sulfamoyl]benzoate (300 mg, 0.75 mmol)in DCM (30 mL) was added BBr₃ (1M in DCM, 3.0 mL, 2.99 mmol) and thereaction mixture was left stirring at room temperature for 2 hrs.Further additions of BBr₃ were made every 2 hrs until both methoxygroups had been removed, as judged by LCMS. The reaction mixture wasquenched with water (60 mL) and diluted with DCM (120 mL). The organicand aqueous layers were separated and the combined aqueous layers werewashed with DCM (2×100 mL). The aqueous later was concentrated in vacuoto half its volume before it was extracted with EtOAc (2×120 mL). TheEtOAc organic layers were combined, dried over Na₂SO₄ and concentratedin vacuo to afford the title compound as a beige solid (150 mg, 49%); ¹HNMR (500 MHz, DMSO) δ 7.72 (m, 1H), 8.02-8.32 (m, 3H), 8.51 (s, 1H).

N-(2-chloro-5-methoxypyrimidin-4-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To a stirring solution of 2,4-dichloro-5-methoxypyrimidine (295 mg, 1.65mmol) in MeCN (10 mL), (3,5-dichlorophenyl)methanesulfonamide (aliterature compound, Bioorganic & Medicinal Chemistry Letters (2005),15(4), 1235-1238, 396 mg, 1.65 mmol) and K₂CO₃ (273 mg, 1.98 mmol) wereadded and the mixture heated under reflux for 18 hrs. The solvent wasremoved under reduced pressure and the residue taken up in DCM (50 mL).Water (15 mL) was added and acidified to approx. pH 2 (2M HCl). Thephases were separated, and the aqueous phase extracted using more DCM(4×50 mL). The organic layers were combined, dried using Na₂SO₄,filtered and concentrated in vacuo to yield the title compound as yellowsolid (450 mg at 40% purity, 29%; m/z=381.9, 383.9 (MH)⁺.

3,4-dichloro-N-(2-chloro-5-methoxypyrimidin-4-yl)benzene-1-sulfonamide

A microwave tube containing 2,4-dichloro-5-methoxypyrimidine (350 mg,1.96 mmol) and 3,4-dichlorobenzene-1-sulfonamide (442 mg, 1.96 mmol) inMeCN (2 mL) was heated at 80° C. in a CEM Discover microwave for 1 min.The solvent was removed in vacuo and the residue dissolved in DCM thenwashed with 0.5M HCl solution, dried over MgSO₄, filtered and thefiltrate evaporated. Silica chromatography (EtOAc in heptane as eluent,20-100%) gave the title compound (400 mg, 55%) m/z=367.8, 369.7 (MH)⁺.

3,5-dichloro-N-(2-chloro-5-methoxypyrimidin-4-yl)benzene-1-sulfonamide

The procedure to prepare3,4-dichloro-N-(2-chloro-5-methoxypyrimidin-4-yl)benzene-1-sulfonamidewas used except that 3,5-dichlorobenzene-1-sulfonamide was substitutedfor 3,4-dichlorobenzene-1-sulfonamide. Microwave heating was at 130° C.for 2×1 hr (37%); m/z=367.8, 369.7 (MH)⁺.

Methyl 3-[(6-chloro-4-methoxypyridazin-3-yl)sulfamoyl]benzoate

To a suspension of 6-chloro-4-methoxypyridazin-3-amine (1.00 g, 6.27mmol) in dry DME (30 mL) was added sodium hydride (60%, 238 mg, 5.85mmol) and the mixture stirred 5 mins. Methyl 3-(chlorosulfonyl)benzoate(1.47 g, 6.27 mmol) was then added and the mixture stirred 1 hr. EtOAcwas added (100 mL) followed by 1M HCl (30 mL) and the phases wereseparated. The organic phase was washed with brine (15 mL), dried(Na₂SO₄), the mixture filtered and the filtrate evaporated to dryness toafford an off white solid containing the title compound (1.84 g at 47%purity, 38% yield); m/z=357.8, 359.9 (MH)⁺.

Methyl 3-[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]benzoate

To a stirred solution of methyl3-[(6-chloro-4-methoxypyridazin-3-yl)sulfamoyl]benzoate (1.3 g, 1.82mmol) in DCM (30 mL) was added 1M BBr₃ in DCM (3.0 mL, 3.0 mmol) and thereaction mixture left under stirring at room temperature for 3 hrs. Thereaction mixture was diluted with DCM (30 mL) and washed with water(2×50 mL). The organic layer was dried over Na₂SO₄ and concentrated invacuo to afford a yellow solid which was a mixture of the title compoundand 3-[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]benzoic acid (480 mg,roughly 1:2 mixture) m/z=343.8, 345.8 (MH)⁺.

3-[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]benzoic acid

To a stirring solution of methyl3-[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]-benzoate (481 mg, 0.70mmol) in EtOH (50 mL) was added NaOH solution (5 M, 0.42 mL, 2.10 mmol)and the mixture stirred at room temperature for 15 mins. The reactionmixture was concentrated in vacuo and the residue acidified with 1M HCland extracted with EtOAc (120 mL). The organic phase was washed withwater (2×80 mL), dried over Na₂SO₄, filtered and the filtrateconcentrated in vacuo to afford the title compound (311 mg, 97%) as ayellow solid m/z=329.8, 331.8 (MH)⁺.

N-(6-chloro-4-methoxypyridazin-3-yl)-1-(4-cyanophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that (4-cyanophenyl)methanesulfonyl chloride wassubstituted for (2-chloro-5-cyanophenyl)methanesulfonyl chloride (40%);¹H NMR (500 MHz, DMSO) δ 3.93 (s, 3H), 5.00 (s, 2H), 7.49 (s, 1H), 7.54(d, 2H), 7.84 (d, 2H).

3-(bromomethyl)-4-fluorobenzonitrile

To a solution 4-fluoro-3-(hydroxymethyl)benzonitrile (1.10 g, 7.0 mmol)in DCM (10 mL) was added PBr₃ (0.76 mL, 7.0 mmol). The reaction mixturestirred for 4 hrs and was then quenched by the slow addition ofsaturated NaHCO₃ until the aqueous phase was neutral. The organic phasewas washed with brine (30 mL), dried (Na₂SO₄), the mixture filtered andthe filtrate evaporated to dryness to afford3-(bromomethyl)-4-fluorobenzonitrile as a yellow solid (800 mg, 50%); ¹HNMR (250 MHz, CDCl₃) δ 4.48 (s, 2H), 7.20 (t, 1H), 7.60-7.67 (m, 1H),7.75 (dd, 1H).

3-[(acetylsulfanyl)methyl]-4-fluorobenzonitrile

The procedure to prepare 3-[(acetylsulfanyl)methyl]-4-chlorobenzonitrilewas used except that 3-(bromomethyl)-4-fluorobenzonitrile wassubstituted for 3-(bromomethyl)-4-chlorobenzonitrile (94%); ¹H NMR (500MHz, DMSO) δ 2.36 (s, 3H), 4.16 (s, 2H), 7.45 (dd, 1H), 7.86 (ddd, 1H),7.92 (dd, 1H).

(5-cyano-2-fluorophenyl)methanesulfonyl chloride

To a stirred solution of N-chlorosuccinimide (2.04 g, 15.3 mmol) inacetonitrile (10 mL) at 0° C. was added 2M HCl (2 mL) followed by asolution of 3-[(acetylsulfanyl)methyl]-4-fluorobenzonitrile (800 mg,3.82 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at0° C. for 30 mins then concentrated under reduced pressure to give awhite solid. Diethyl ether (20 mL) was added and the mixture sonicated,then filtered. The filtrate was then concentrated to afford the titlecompound as a white solid (84%); ¹H NMR (500 MHz, DMSO) δ 3.79 (s, 2H),7.27-7.46 (m, 1H), 7.78 (ddd, 1H), 7.87 (dd, 1H).

N-(6-chloro-4-methoxypyridazin-3-yl)-1-(5-cyano-2-fluorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamidewas used except that (5-cyano-2-fluorophenyl)methanesulfonyl chloridewas substituted for (2-chloro-5-cyanophenyl) methanesulfonyl chloride(15%); m/z 356.6, 358.6 (MH)⁺.

3-fluoro-5-(hydroxymethyl)benzonitrile

To a solution of 3-cyano-5-fluorobenzoic acid (2 g, 0.01 mol) stirringin anhydrous THF (40 mL) was added carbonyl diimidazole (2.16 g, 0.01mol) and the reaction mixture left to stir at room temperature for 3 hrsunder a nitrogen atmosphere.

The reaction mixture was cooled to 0° C. and NaBH₄ (1.37 g, 0.04 mol)was added portion wise over 30 mins and the reaction mixture stirred fora further 1 hr at 0° C. before being allowed to warm to room temperatureand stirred for another 1 hr. It was then cooled to 0° C. and quenchedwith saturated ammonium chloride. The mixture was concentrated underreduced pressure to remove the THF and the resultant aqueous suspensionextracted into EtOAc (3×25 mL). The organics were combined and washedwith brine (3×15 mL), dried over MgSO₄ and concentrated to afford ayellow oil which was purified by silica chromatography (heptane:EtOAc,eluent: 35% EtOAc), to afford the title compound as a white solid (1.22g, 65%); ¹H NMR (500 MHz, DMSO) δ 4.56 (d, 2H), 5.53 (t, 1H), 7.48-7.54(m, 1H), 7.61 (s, 1H), 7.68-7.73 (m, 1H).

3-(bromomethyl)-5-fluorobenzonitrile

The procedure to prepare 3-(bromomethyl)-4-chlorobenzonitrile was usedexcept that 3-fluoro-5-(hydroxymethyl)benzonitrile was substituted for4-chloro-3-(hydroxymethyl)benzonitrile (50%); ¹H NMR (500 MHz, DMSO) δ4.73 (s, 2H), 7.70-7.75 (m, 1H), 7.80-7.84 (m, 2H).

3-[(acetylsulfanyl)methyl]-5-fluorobenzonitrile

The procedure to prepare 3-[(acetylsulfanyl)methyl]-4-chlorobenzonitrilewas used except that 3-(bromomethyl)-5-fluorobenzonitrile wassubstituted for 3-(bromomethyl)-4-chlorobenzonitrile (89%); ¹H NMR (500MHz, DMSO) δ 2.37 (s, 3H), 4.17 (s, 2H), 7.50-7.57 (m, 1H), 7.64 (s,1H), 7.69-7.82 (m, 1H).

(3-cyano-5-fluorophenyl)methanesulfonyl chloride

The procedure to prepare (5-cyano-2-fluorophenyl)methanesulfonylchloride was used except that3-[(acetylsulfanyl)methyl]-5-fluorobenzonitrile was substituted for3-[(acetylsulfanyl)methyl]-4-fluorobenzonitrile (73%); ¹H NMR (500 MHz,DMSO) δ 3.81 (s, 2H), 7.52 (d, 1H), 7.59 (s, 1H), 7.68 (ddd, 1H).

N-(6-chloro-4-methoxypyridazin-3-yl)-1-(3-cyano-5-fluorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamidewas used except that (3-cyano-5-fluorophenyl)methanesulfonyl chloridewas substituted for (2-chloro-5-cyanophenyl) methanesulfonyl chloride(15%); m/z 356.6, 358.6 (MH)⁺.

(2-chloro-5-cyanophenyl)methanesulfonamide

To a stirring solution of (2-chloro-5-cyanophenyl)methanesulfonylchloride (500 mg, 2.0 mmol) in DCM (15 mL) was added ammonium hydroxide(0.76 mL, 20 mmol) the mixture stirred at room temperature for 16 hrs.Water (20 mL) was added and the solution acidified to approx. pH 2 using1M HCl. The mixture was extracted using DCM (3×30 mL), dried (Na₂SO₄),filtered and the filtrate concentrated in vacuo to yield the titlecompound as a white solid (400 mg, 70%); ¹H NMR (250 MHz, DMSO) δ 4.51(s, 2H), 7.11 (s, 2H), 7.74 (d, 1H), 7.87 (dd, 1H), 7.93 (d, 1H).

1-(2-chloro-5-cyanophenyl)-N-(2-chloro-5-methoxypyrimidin-4-yl)methanesulfonamide

The procedure to prepare3,4-dichloro-N-(2-chloro-5-methoxypyrimidin-4-yl)benzene-1-sulfonamidewas used except that (2-chloro-5-cyanophenyl)methanesulfonamide wassubstituted for 3,4-dichlorobenzene-1-sulfonamide and microwave heatingwas at 135° C. for 2.5 hrs (30%); m/z=372.8, 374.8 (MH)⁺.

2-chloro-N-(6-chloro-4-methoxypyridazin-3-yl)-4-cyanobenzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamidewas used except that 2-chloro-4-cyanobenzenesulfonyl chloride wassubstituted for (2-chloro-5-cyanophenyl) methanesulfonyl chloride (38%);m/z=358.9, 360.9 (MH)⁺.

3-chloro-N-(6-chloro-4-methoxypyridazin-3-yl)-4-fluorobenzene-1-sulfonamide

To a suspension of NaH (60%, 25 mg, 0.63 mmol) in THF (5 mL) at 0° C.was added 6-chloro-4-methoxypyridazin-3-amine (100 mg, 0.63 mmol) wasadded and stirred for 30 minutes, 3-chloro-4-fluorobenzenesulfonylchloride (144 mg, 0.63 mmol) was added and the reaction mixture wasstirred for 3 hrs at room temperature. The THF was removed under reducedpressure and the residue was taken up in EtOAc and washed with 1M HCl(2×10 mL). The organic layer was dried using Na₂SO₄, filtered andconcentrated in vacuo to yield a brown residue which was purified usingsilica column chromatography (Gradient: EtOAc in heptane, 0 to 100%EtOAc) to yield the title compound as an off white solid (19%);m/z=351.8, 353.8 (MH)⁺.

3-chloro-N-(6-chloro-4-methoxypyridazin-3-yl)-5-fluorobenzene-1-sulfonamide

The procedure to prepare3-chloro-N-(6-chloro-4-methoxypyridazin-3-yl)-4-fluorobenzene-1-sulfonamidewas used except that 3-chloro-5-fluorobenzenesulfonyl chloride wassubstituted for 3-chloro-4-fluorobenzenesulfonyl chloride (21%);m/z=351.8, 353.8 (MH)⁺.

4-methoxy-2-(methylsulfanyl)-5-nitropyridine

To a solution of 2-chloro-4-methoxy-5-nitropyridine (500 mg, 2.65 mmol)in anhydrous DMF (10 mL) at 0° C. was added sodium methanethiolate (220mg, 3.18 mmol) portion-wise over 5 mins. The reaction mixture wasallowed to warm to room temperature and then stirred for a further 2hrs. A further portion of sodium methanethiolate (110 mg, 1.59 mmol) wasadded and the mixture left to stir for a further 1 hr. Water (50 mL) wasadded followed by DCM (100 mL). The phases were separated and theorganic phase was washed with water (2×20 mL) brine (20 mL) and driedover Na₂SO₄. The filtrate was evaporated to dryness to afford the titlecompound as an off white solid (512 mg, 96%); ¹H NMR (500 MHz, DMSO-d6)δ 2.60 (s, 3H), 4.01 (s, 3H), 7.24 (s, 1H), 8.90 (s, 1H).

2-methanesulfonyl-4-methoxy-5-nitropyridine

To a solution of 4-methoxy-2-(methylsulfanyl)-5-nitropyridine (510 mg,2.55 mmol) in methanol (12 mL) was added OXONE (5:1:1:2) (1.56 g, 2.55mmol) as a solution in water (15 mL) drop-wise. The resulting reactionmixture (which formed a white precipitate on addition) was stirred at50° C. for 1 hr. A further portion of Oxone (1.56 g, 2.55 mmol) wasadded and the mixture was stirred for a further 1 hr at 50° C. Thesolvent was partially evaporated and the aqueous residue extracted withDCM (50 mL). The organic phase was dried (Na₂SO₄), filtered andconcentrated under reduced pressure to obtain the title compound as anoff-white solid (650 mg, 109%); m/z=232.9 (MH)⁺.

6-methanesulfonyl-4-methoxypyridin-3-amine

To a solution of 2-methanesulfonyl-4-methoxy-5-nitropyridine (650 mg,2.80 mmol) in a mixture of MeOH (4 mL), water (4 mL) and concentratedHCl (0.3 mL) was added iron powder (630 mg, 11.2 mmol). The resultingsuspension was stirred at 80° C. for 2 hrs then cooled to roomtemperature and filtered through a pad of Celite. The solid was washedfurther with MeOH and the collected filtrate evaporated to dryness toafford a light yellow solid containing the title compound (599 mg, >100%due to presence of iron residues); m/z=202.9 (MH)⁺.

3,5-dichloro-N-(6-methanesulfonyl-4-methoxypyridin-3-yl)benzene-1-sulfonamide

To a solution of 6-methanesulfonyl-4-methoxypyridin-3-amine (400 mg,1.98 mmol) in pyridine (10 mL) was added 3,5-dichlorobenzene-1-sulfonylchloride (243 mg, 0.99 mmol) portionwise. The resulting reaction mixturewas stirred at room temperature under nitrogen for 2 hrs then evaporatedto dryness, the residue re-dissolved in EtOAc (50 mL) and washed withwater (25 mL) followed by saturated NaHCO₃ (25 mL) (to remove sulfonicacid residues). The combined aqueous layers were back-extracted andcombined organics were dried over MgSO₄ and evaporated to dryness. Theresulting crude residue was purified by silica chromatography (eluent:heptane:EtOAc 20-50%) to afford the title compound as a yellow solid(185 mg, 22%); ¹H NMR (500 MHz, DMSO-d6) δ 3.26 (s, 3H), 3.81 (s, 3H),7.58 (s, 1H), 7.81 (d, 2H), 8.00 (t, 1H), 8.45 (s, 1H).

3,5-dichloro-N-(6-chloro-4-methoxypyridin-3-yl)benzene-1-sulfonamide

The procedure to prepare3,5-dichloro-N-(6-methanesulfonyl-4-methoxypyridin-3-yl)benzene-1-sulfonamidewas used except that 6-chloro-4-methoxypyridin-3-amine was substitutedfor 6-methanesulfonyl-4-methoxypyridin-3-amine; m/z=366.7, 368.7 (MH)⁺.

1-(3,5-dichlorophenyl)-N-[5-methoxy-2-(trifluoromethyl)pyrimidin-4-yl]methanesulfonamide

The procedure to prepare3,4-dichloro-N-(2-chloro-5-methoxypyrimidin-4-yl)benzene-1-sulfonamidewas used except that (3,5-dichlorophenyl)methanesulfonamide wassubstituted for 3,4-dichlorobenzene-1-sulfonamide,4-chloro-5-methoxy-2-(trifluoromethyl)pyrimidine was substituted for2,4-dichloro-5-methoxypyrimidine and microwave heating was at 120° C.for 2 hrs (66%); m/z=415.8, 417.8 (MH)⁺.

3-chloro-5-fluorobenzene-1-sulfonamide

3-chloro-5-fluorobenzene-1-sulfonyl chloride (100 mg, 0.437 mmol) wassuspended in DCM (5 mL) and stirred at room temperature. Ammoniumhydroxide (0.165 mL) was added and the solution was stirred at roomtemperature for 2 hrs. Saturated ammonium chloride (5 mL) added. Thelayers were separated and the aqueous was extracted with DCM (2×20 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated toa solid containing the title compound; m/z=208.0, 210.0 (MH)⁺.

3-chloro-5-fluoro-N-[5-methoxy-2-(trifluoromethyl)pyrimidin-4-yl]benzene-1-sulfonamide

The procedure to prepare3,4-dichloro-N-(2-chloro-5-methoxypyrimidin-4-yl)benzene-1-sulfonamidewas used except that that 3-chloro-5-fluorobenzene-1-sulfonamide wassubstituted for 3,4-dichlorobenzene-1-sulfonamide,4-chloro-5-methoxy-2-(trifluoromethyl)pyrimidine was substituted for2,4-dichloro-5-methoxypyrimidine and microwave heating was at 120° C.for 2 hrs (66%); m/z=385.8, 387.8 (MH)⁺.

N-(5-bromo-3-hydroxypyrazin-2-yl)-3,5-dichlorobenzene-1-sulfonamide

To a stirred suspension of sodium hydride (60%, 196 mg, 4.9 mmol) andTHF (10 mL) at 0° C., under N₂, was added5-bromo-3-methoxypyrazin-2-amine (1.00 g, 4.9 mmol) in one portion. Thiswas stirred at 0° C. for 30 min before the addition of3,5-dichlorobenzene-1-sulfonyl chloride (120 mg, 0.49 mmol) in oneportion. The reaction was allowed to warm to room temperature andstirred for 2 hrs. The reaction was acidified to pH 2 with 2 M HCl,diluted with water (100 mL) and extracted with EtOAc (100 ml×3). Thecombined organic extracts were washed with water (100 ml), brine (100ml), dried (Na₂SO₄), filtered and concentrated to give the crude productas a brown oil, which was purified using silica chromatography (eluent12% to 50% EtOAc in heptane) to give the title compound as a white solid(866 mg, 39%); m/z=411.7, 413.6 (MH)+

3,5-dichloro-N-[3-methoxy-5-(methylsulfanyl)pyrazin-2-yl]benzene-1-sulfonamide

The procedure for preparation of1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propylsulfanyl)pyridazin-3-yl]methanesulfonamide was used except thatN-(5-bromo-3-hydroxypyrazin-2-yl)-3,5-dichlorobenzene-1-sulfonamide wassubstituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamideand sodium methanethiolate was substituted for propane-1-thiol; (94% ¹HNMR (500 MHz, DMSO-d6) δ 3.93 (s, 3H), 7.73 (s, 1H), 7.89-7.92 (m, 2H),7.95-7.99 (m, 1H).

3,5-dichloro-N-(5-methanesulfonyl-3-methoxypyrazin-2-yl)benzene-1-sulfonamide

The procedure to prepare 2-methanesulfonyl-4-methoxy-5-nitropyridine wasused except that3,5-dichloro-N-[3-methoxy-5-(methylsulfanyl)pyrazin-2-yl]benzene-1-sulfonamidewas substituted for 4-methoxy-2-(methylsulfanyl)-5-nitropyridine.Extraction was with EtOAc rather than DCM (65%); ¹H NMR (250 MHz,DMSO-d6) δ 3.18 (s, 3H), 3.97 (s, 3H), 7.90-7.99 (m, 3H), 8.14 (s, 1H).

2-chloro-4-cyanobenzene-1-sulfonyl Chloride

Thionyl chloride (15 mL) was dropped into water (60 mL) with stirringand cooling so that the temperature did not rise above −5° C. Copper(I)chloride (19 mg) was then added.

In parallel, 4-amino-3-chlorobenzonitrile (1.50 g, 9.83 mmol) wasdissolved in conc. HCl (30 mL), cooled to −5° C. whereupon a solution ofsodium nitrite (746 mg, 10.8 mmol) in water (15 mL) was added. Aftercomplete addition the solution of diazonium salt was added in over 2mins to the first solution, both at −5 to 0° C. (gas evolution wasobserved) and a foam formed on top of the solution. The temperature wasallowed to come to room temperature and the aqueous phase was thenextracted with DCM (3×70 ml). The combined organic phase was washed withbrine (5 mL), dried (Na₂SO₄), the mixture filtered and the filtrateevaporated to dryness to afford a yellow solid containing the titlecompound (1.88 g, 88%); ¹H NMR (500 MHz, CDCl₃) δ 7.83 (dd, 1H), 7.97(d, 1H), 8.31 (d, 1H).

2-chloro-N-(6-chloro-4-methoxypyridazin-3-yl)-4-cyanobenzene-1-sulfonamide

The procedure to prepare5-bromo-6-chloro-N-(6-chloro-4-methoxypyridazin-3-yl)pyridine-3-sulfonamidewas used except that 2-chloro-4-cyanobenzene-1-sulfonyl chloride wassubstituted for 5-bromo-6-chloropyridine-3-sulfonyl chloride (46%);m/z=359.0, 361.0 (MH)⁺.

3-chloro-4-[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]benzoic acid

A suspension of2-chloro-N-(6-chloro-4-methoxypyridazin-3-yl)-4-cyanobenzene-1-sulfonamide(480 mg, 1.34 mmol) was refluxed for 2 hrs in concentrated HCl. Thecooled reaction mixture was diluted with water (25 mL) and filtered. Thesolid was washed in more water and dried in air to afford the titlecompound as a tan solid (62%); m/z=363.8, 365.8 (MH)⁺.

Methyl 3-chloro-5-(diethylcarbamoyl)benzoate

To a solution of 1,3-dimethyl 5-chlorobenzene-1,3-dicarboxylate (4.00 g,17.5 mmol) in dioxane (50 mL) and water (50 mL) was added NaOH (700 mg,17.5 mmol). The resulting suspension was stirred vigorously at 40° C.for 2 hrs and then for a further 16 hrs at room temperature. Thereaction mixture was evaporated to dryness, re-dissolved in water (˜200mL) and acidified to pH 3 using 1M HCl. The resulting white precipitatewas sonicated for 2 mins and filtered. The white solid was washedfurther with water and then dried in a vacuum oven overnight. Thisafforded a white solid (3.6 g) which was a mixture of 3 productsincluding 3-chloro-5-(methoxycarbonyl)benzoic acid.

This solid was dissolved in DMF (150 mL) at 0° C. and diethylamine (2.56g, 0.03 mol), DIPEA (6.09 ml, 0.03 mol) and HATU (6.64 g, 0.02 mol) wereadded. The reaction mixture was then stirred at room temperature for 6hrs then evaporated to dryness, re-dissolved in EtOAc (200 mL) andwashed with water (3×200 mL) and brine (2×200 mL). The combined organicswere then dried over MgSO₄ and evaporated to dryness to afford the crudeproduct. This was purified by silica chromatography (Biotage: 100 g SNAPcartridge) eluting with 0-80% EtOAc in heptane to afford the titlecompound as a colourless oil (880 mg (28%); ¹H NMR (500 MHz, CDCl₃) δ1.13 (br. s, 3H), 1.26 (t, 3H), 3.24 (br.s, 2H), 3.54 (br. s, 2H), 3.93(s, 3H), 7.55 (m, 1H), 7.92 (m, 1H), 8.04 (m, 1H).

3-chloro-N,N-diethyl-5-(hydroxymethyl)benzamide

To a solution of methyl 3-chloro-5-(diethylcarbamoyl)benzoate (880 mg,3.26 mmol) in DCM (50 mL) and MeOH (50 mL) at 0° C. under nitrogen wasadded NaBH₄ (247 mg, 6.53 mmol). The resulting solution was allowed towarm to room temperature and then stirred for 4 hrs. More NaBH₄ (247 mg,6.53 mmol) was added and the reaction mixture was left to stir atambient temperature for 48 hrs then quenched at 0° C. with saturatedNH₄Cl (10 mL) and then extracted into EtOAc (3×50 mL). Combined organicswere dried over MgSO₄ and evaporated to dryness.

The residue (a mixture of starting material and desired product) wasre-dissolved in THF (50 mL) and MeOH (10 mL). More NaBH₄ (247 mg, 6.53mmol) was added at 0° C. and then the reaction mixture was heated at 50°C. for 2 hrs. A final portion of NaBH₄ (247 mg, 6.53 mmol) was added andthe mixture was stirred for a further 2 hrs at 50° C.

The reaction mixture was cooled to 0° C., quenched with saturated NH₄Cl(20 mL) and evaporated to approx. 20 mL. The resulting solution wasdiluted with water (50 mL) and extracted into EtOAc (3×50 mL). Combinedorganics were dried over MgSO₄ and evaporated to dryness to afford thetitle compound as a yellow oil (741 mg, 94%); ¹H NMR (500 MHz, CDCl₃) δ1.11 (br. s, 3H), 1.25 (br. s, 3H), 3.23 (s, 2H), 3.53 (s, 2H), 4.66 (s,2H), 7.20 (s, 1H), 7.24 (s, 1H), 7.37 (s, 1H).

3-(bromomethyl)-5-chloro-N,N-diethylbenzamide

The procedure to prepare 3-(bromomethyl)-4-chlorobenzonitrile was usedexcept that 3-chloro-N,N-diethyl-5-(hydroxymethyl)benzamide wassubstituted for 4-chloro-3-(hydroxymethyl)benzonitrile (79%); ¹H NMR(500 MHz, CDCl₃) δ 1.13 (br.s, 3H), 1.25 (br.s, 4H), 3.24 (s, 2H), 3.53(s, 2H), 4.43 (s, 2H), 7.27-7.29 (m, 2H), 7.41 (d, 1H).

3-[(acetylsulfanyl)methyl]-5-chloro-N,N-diethylbenzamide

The procedure to prepare 3-[(acetylsulfanyl)methyl]-4-chlorobenzonitrilewas used except that 3-(bromomethyl)-5-chloro-N,N-diethylbenzamide wassubstituted for 3-(bromomethyl)-4-chlorobenzonitrile (98%); ¹H NMR (500MHz, CDCl₃) δ 1.11 (br. s, 3H), 1.17-1.30 (br. m, 3H), 2.36 (s, 3H),3.22 (br. s, 2H), 3.52 (br. s, 2H), 4.07 (s, 2H), 7.17 (m, 1H), 7.23 (m,1H), 7.31 (m, 1H).

3-chloro-5-{[(6-chloro-4-methoxypyridazin-3-yl)sulfamoyl]methyl}-N,N-diethylbenzamide

A solution of 3-[(acetylsulfanyl)methyl]-5-chloro-N,N-diethylbenzamide(695 mg, 2.32 mmol) in acetic acid (10 mL) and water (2 mL) at roomtemperature was saturated with chlorine gas with stirring until thedisappearance of starting material was observed by TLC (1:1EtOAc/heptane). The reaction mixture was diluted with EtOAc (50 mL) andbrine (50 mL). The phases were separated and the organic phase waswashed with brine (2×25 mL), dried (Na₂SO₄) and the mixture filtered andthe filtrate evaporated to dryness to afford the intermediate sulfonylchloride as a yellow oil which was used immediately in the followingreaction (700 mg, 93%).

To a solution of 6-chloro-4-methoxypyridazin-3-amine (344 mg, 2.16 mmol)in anhydrous THF (30 mL) at 0° C. under nitrogen was added NaH (60%, 104mg, 2.59 mmol). The resulting solution was stirred at 0° C. for 30 minsand then the intermediate sulfonyl chloride (700 mg, 2.16 mmol) inanhydrous THF (2 mL) was added. The resulting reaction mixture wasstirred at room temperature for 16 hrs then quenched with saturatedNH₄Cl (approx. 10 mL), diluted with water (50 mL), acidified to pH 5using 1M HCl and extracted into EtOAc (3×50 mL). The combined organicswere dried over MgSO4 and evaporated to dryness to afford the titlecompound as a dark yellow solid (360 mg, 37%); m/z=446.9, 448.9 (MH)⁺.

N-(6-chloro-4-methoxypyridazin-3-yl)-3-cyano-5-fluorobenzene-1-sulfonamide

The procedure to prepare5-bromo-6-chloro-N-(6-chloro-4-methoxypyridazin-3-yl)pyridine-3-sulfonamidewas used except that 3-cyano-5-fluorobenzene-1-sulfonyl chloride wassubstituted for 5-bromo-6-chloropyridine-3-sulfonyl chloride (yield notdetermined). 4-bromo-6-(trifluoromethyl)pyridazin-3-amine

To a solution of 6-(trifluoromethyl)pyridazin-3-amine (480 mg, 0.003mol)) and sodium hydrogencarbonate (297 mg, 0.004 mol) in MeOH (10 mL)was added bromine (0.159 mL, 0.003 mol). The reaction mixture wasstirred at room temperature for 2 hrs before the solvent was evaporated,water (30 mL) added and the solid produced isolated by filtration. Thesolid obtained was dried under vacuum to afford the title compound as abrown solid (671 mg, 89%); ¹H NMR (500 MHz, CDCl₃) 5.69 (s, 2H), 7.73(s, 1H).

4-methoxy-6-(trifluoromethyl)pyridazin-3-amine

To a solution of 4-bromo-6-(trifluoromethyl)pyridazin-3-amine (671 mg,2.63 mmol) in MeOH (10 mL) was added sodium methoxide (5.4M in MeOH,3.16 mmol) and the solution stirred at 90° C. for 1.5 hrs. The MeOH wasevaporated, water (100 mL) added and the mixture filtered. The crudebrown solid was purified using silica chromatography (0-100% ethylacetate in heptane) to afford the title compound (230 mg, 45%); ¹H NMR(500 MHz, CDCl₃) δ 4.03 (s, 3H), 5.49 (s, 2H), 6.91 (s, 1H).

(3,4-dichlorophenyl)methanesulfonamide

The procedure to prepare 3-chloro-5-fluorobenzene-1-sulfonamide was usedexcept that (3,4-dichlorophenyl)methanesulfonyl chloride was substitutedfor 3-chloro-5-fluorobenzene-1-sulfonyl chloride (94%); ¹H NMR (250 MHz,DMSO) δ 4.32 (s, 2H), 6.93 (s, 2H), 7.36 (dd, 1H), 7.60-7.69 (m, 2H).

1-(3,4-dichlorophenyl)-N-[5-methoxy-2-(trifluoromethyl)pyrimidin-4-yl]methanesulfonamide

The procedure to prepare3,4-dichloro-N-(2-chloro-5-methoxypyrimidin-4-yl)benzene-1-sulfonamidewas used except that that (3,4-dichlorophenyl)methanesulfonamide wassubstituted for 3,4-dichlorobenzene-1-sulfonamide,4-chloro-5-methoxy-2-(trifluoromethyl)pyrimidine was substituted for2,4-dichloro-5-methoxypyrimidine and microwave heating was at 140° C.for 2 hrs (83%); m/z=415.8, 417.8 (MH)⁺.

N-(6-chloro-4-methoxypyridazin-3-yl)-1-(2,5-dichlorothiophen-3-yl)methane-sulfonamide

The procedure to prepareN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamidewas used except that (2,5-dichlorothiophen-3-yl)methanesulfonyl chloridewas substituted for (2-chloro-5-cyanophenyl)methane-sulfonyl chloride(27%); ¹H NMR (500 MHz, DMSO) δ 3.94 (s, 3H), 4.84 (s, 2H), 7.11 (s,1H), 7.46 (s, 1H).

3,5-dichloro-N-(6-iodo-4-methoxypyridazin-3-yl)benzene-1-sulfonamide

To a solution of 6-iodo-4-methoxypyridazin-3-amine (1.35 g, 5.38 mmol,but containing large amounts of the bromo byproduct) stirring inanhydrous THF (10 mL) at 0° C. was added NaH (60%, 215 mg, 5.38 mmol).The reaction mixture was allowed to stir for 30 mins. After this time3,5-dichlorobenzenesulfonyl chloride (1.32 g, 5.38 mmol) was addedportion wise and the mixture stirred for 2 hrs. It was then cooled to 0°C. and quenched with saturated ammonium chloride. Once effervescence hadceased the mixture was allowed to warm to room temperature and stirredfor a further 15 min then extracted with EtOAc (3×25 mL). The combinedorganics were washed with brine (20 mL) and dried over MgSO₄ thenconcentrated under reduced pressure. Purification was successfullyachieved by silica chromatography (0-100% EtOAc in heptane) to affordthe title compound (also containing the bromo analogue) as a grey solid(300 mg, 12%); m/z=413.6, 459.7 (MH)⁺.

3,5-dichloro-N-[4-methoxy-6-(methylsulfanyl)pyridazin-3-yl]benzene-1-sulfonamide

The procedure for preparation of1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propylsulfanyl)pyridazin-3-yl]methanesulfonamide was used except that3,5-dichloro-N-(6-iodo-4-methoxypyridazin-3-yl)benzene-1-sulfonamide wassubstituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamideand sodium methanethiolate was substituted for propane-1-thiol (35%); 1HNMR (500 MHz, DMSO) δ 2.53 (s, 3H), 3.87 (s, 3H), 7.28 (s, 1H),7.80-7.95 (m, 3H).

3,5-dichloro-N-(6-methanesulfonyl-4-methoxypyridazin-3-yl)benzene-1-sulfonamide

The procedure to prepare 2-methanesulfonyl-4-methoxy-5-nitropyridine wasused except that3,5-dichloro-N-[4-methoxy-6-(methylsulfanyl)pyridazin-3-yl]benzene-1-sulfonamidewas substituted for 4-methoxy-2-(methylsulfanyl)-5-nitropyridine.Heating was at 60° C. for 2 hrs (54%); m/z=411.8, 413.8 (MH)⁺.

4-amino-2-chloro-3-methoxypyridine

The procedure for preparation of 3-amino-5-chloro-4-hydroxy-pyridine wasused except that 2-chloro-3-methoxy-4-nitropyridine was substituted for3-chloro-4-hydroxy-5-nitropyridine. ¹H NMR (500 mHz, DMSO) δ 3.68 (s,3H), 6.3 (bs, 2H), 6.59 (d, 1H), 7.60 (d, 1H).

3-amino-5-chloropyridin-4-ol

A solution of 3-chloro-4-hydroxy-5-nitropyridine (7.31 g, 42 mmol) inMeOH (400 mL) was treated with RaneyNi (1 teaspoon) and hydrogenated for8 hrs at atmospheric pressure. The mixture was filtered through Celitecarefully without drying out the celite/residue and the filtrateevaporated to dryness to afford 3-amino-5-chloro-4-hydroxy-pyridine as adark purple solid (5.8 g at 95% purity, 96% yield); ¹H NMR (500 mHz,DMSO) δ 4.79 (bs, 2H), 7.13 (s, 1H), 7.76 (s, 1H), 11.50 (bs, 1H).

3-amino-6-chloro-2-methoxypyridine

The title compound was prepared from commercial 2,6-dichloropyridine bythe following sequence; nitration at 120° C. in a mixture of fumingnitric acid and conc. sulfuric acid (1/2) followed by reaction with 1.0equiv. methanol and sodium hydride in THF. Reduction of the nitro groupwas accomplished using hydrogen gas and Raney nickel in THF. H-nmr for3-amino-6-chloro-2-methoxypyridine; (500 mHz, DMSO) δ 3.88 (s, 3H), 5.09(bs, 2H), 6.79 (d, 1H), 6.93 (d, 1H).

3-amino-6-ethanesulfonyl-2-methoxypyridine

The title compound was prepared from commercial 2,6-dichloropyridineusing the following sequence; nitration at 120° C. in a mixture offuming nitric acid and conc. sulfuric acid (1/2) followed by reactionwith sodium ethanethiolate in THF and oxidation with Oxone inethanol/water. Reduction of the nitro group was accomplished usinghydrogen and Raney nickel in THF. H-nmr for3-amino-6-ethanesulfonyl-2-methoxypyridine; (500 mHz, DMSO) δ 1.12 (t,3H), 3.26 (q, 2H), 3.96 (s, 3H), 6.07 (bs, 2H), 6.98 (d, 1H), 7.44 (d,1H).

1-(5,6-dichloropyridin-3-yl)methanesulfonylchloride

The title compound was prepared as a crystalline solid from comm.5,6-dichloronicotinic acid using the sequence; formation of thecarboxylic acid chloride using oxalyl chloride and cat. DMF indichloromethane followed by reduction with sodium borohydride in water,then reaction with phosphorus oxychloride/DMF in chloroform to give thechloromethylpyridine followed by substitution with thioaceticacid/potassium carbonate in acetone and finally chlorosulfonylationusing NCS in acetonitrile/water/hydrochloric acid. H-nmr for1-(5,6-dichloropyridin-3-yl)methanesulfonylchloride; (500 mHz, DMSO) δ3.83 (s, 2H), 8.07 (s, 1H), 8.30 (s, 1H).

3-amino-5,6-dichloro-2-methoxypyridine

The title compound was prepared from 3-amino-5-chloro-2-methoxypyridine(commercial) by chlorination with 1 equiv. NCS in DMF. After stirringfor 18 h at room temperature the mixture was partitioned betweendichloromethane and water, the organic phase was concentrated andpurified by flash chromatography (SiO₂, ethyl acetate/heptane; 1:10)which gave the title compound in 15% yield. H-nmr for3-amino-5,6-dichloro-2-methoxypyridine; (500 mHz, DMSO) δ 3.84 (s, 3H),5.44 (bs, 2H), 7.04 (s, 1H).

4-fluoro-3-(hydroxymethyl)benzonitrile

A solution of 5-cyano-2-fluorobenzoic acid (1.90 g, 11.5 mmol) inthionyl chloride (7 mL, 96.5 mmol) was refluxed for 3 hrs. The excessthionyl chloride was evaporated. The residue was dissolved in EtOH (20ml) and THF (15 ml). Sodium borohydride (1.31 g, 34.5 mmol) was addedslowly at 0° C. The reaction mixture was stirred for 1 hr at 0° C. andthen for 3 days at room temperature. The reaction was quenched by theaddition of water (50 mL) and was extracted with EtOAc (3×50 mL). Thecombined organic extracts were washed with water (50 mL) and brine (50mL), dried (Na₂SO₄), the mixture filtered and the filtrate evaporated todryness. The crude product was purified using silica chromatography(eluent 0% to 10% MeOH in DCM) to give4-fluoro-3-(hydroxymethyl)benzonitrile as a yellow solid (1.10 g, 60%);¹H NMR (500 MHz, CDCl₃) δ 4.81 (s, 2H), 7.13-7.17 (m, 1H), 7.58-7.62 (m,1H), 7.84 (dd, 1H).

N-(5-cyano-3-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

A suspension of1-(3,5-dichlorophenyl)-N-(5-iodo-3-methoxypyridin-2-yl)methanesulfonamide(200 mg, 0.42 mmol) and copper(I) cyanide (189 mg, 2.11 mmol) in NMP (4mL) was heated at 145° C. for 3 hrs. The cooled reaction mixture waspartitioned between EtOAc (100 mL) and water (30 mL). The phases wereseparated and the organic phase was washed with water (3×15 mL) andbrine (5 mL), dried (Na₂SO₄), the mixture filtered and the filtrateevaporated to dryness to affordN-(5-cyano-3-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamideas a brown oil which was used in the next step without furtherpurification (183 mg, 91%); m/z=371.8, 373.8 (MH)⁺.

5-chloro-6-methylpyridine-3-sulfonyl chloride

Thionyl chloride (3 mL) was added dropwise into water with mixing andcooling so that the temperature did not rise above −5° C. Copper(I)chloride (3 mg, 0.04 mmol) was then added. In parallel,5-chloro-6-methylpyridin-3-amine (250 mg, 1.75 mmol), prepared by aliterature method (PCT Int. Appl., 2006067445, 29 Jun. 2006) wasdissolved in conc. HCl (6 mL), cooled to −5° C. whereupon a solution ofsodium nitrite (133 mg, 1.93 mmol) in water (4 mL) was added to form thediazonium salt. With both solutions cooled at −5 to 0° C., the solutionof diazonium salt was added to the first solution over 2 min. Afterstirring for 30 min, the reaction mixture was taken to pH 7 by additionof NaHCO₃. The aqueous phase was extracted with DCM (3×70 mL). Thecombined organic phases were washed with brine (5 mL), dried (Na₂SO₄),the mixture filtered and the filtrate evaporated to dryness to afford5-chloro-6-methylpyridine-3-sulfonyl chloride as a green oil (256 mg,58%); ¹H NMR (500 MHz, CDCl₃) δ 2.71 (s, 3H), 8.16 (d, 1H), 8.92 (d,1H).

N-(5-chloro-3-methoxypyridin-2-yl)-5-phenylpyridine-3-sulfonamide

A flask charged with5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide (300mg, 0.79 mmol), phenylboronic acid (97 mg, 0.79 mmol) 1,4-dioxane (5 mL)and 2M Na₂CO₃ (0.6 mL) and tetrakis(triphenylphosphane)palladium(0) (10mg, 0.01 mmol) was degassed with argon and then heated at 80° C. for 3hrs. The mixture was then diluted with EtOAc (10 mL) and water (10 mL).The organic layer was washed with brine, dried (Na₂SO₄), the mixture wasfiltered and the filtrate evaporated to dryness. The crude product waspurified using silica chromatography (eluent 10% MeOH in DCM) to giveN-(5-chloro-3-methoxypyridin-2-yl)-5-phenylpyridine-3-sulfonamide (150mg, 50%); m/z=376.4 (MH)⁺.

Example 15-bromo-6-chloro-N-(5-chloro-2-hydroxypyridin-3-yl)pyridine-3-sulfonamide

5-bromo-6-chloro-N-(5-chloro-2-methoxypyridin-3-yl)pyridine-3-sulfonamide(250 mg, 0.605 mmol) was dissolved in DCM (15 mL) and the reactionmixture cooled to −10° C. followed by addition of neat BBr₃ (454 mg,1.82 mmol) drop wise. The reaction mixture was then stirred at roomtemperature for 16 hrs, diluted with DCM (5 mL) and neutralized withsodium bicarbonate to pH 7-8. More DCM (5 mL) was added, the phases wereseparated, the organic phase was washed with brine (15 mL), dried(Na₂SO₄) filtered and the filtrate concentrated under vacuum to affordthe crude compound which was chromatographed on silica (5% Methanol inDCM) to afford5-bromo-6-chloro-N-(5-chloro-2-hydroxypyridin-3-yl)pyridine-3-sulfonamide(90 mg, 37%) as a white solid.

Example 2 N-(4-hydroxypyridin-3-yl)benzenesulfonamide

To a stirred solution of 3-amino-pyridin-4-ol (94 mg, 0.850 mmol) in DCM(4 mL) and DIPEA (220 mg, 1.70 mmol) at 0° C., was added dropwise asolution of benzene-sulfonyl chloride (150 mg, 0.85 mmol) in DCM (4 mL)under nitrogen. The reaction mixture was warmed to room temperature andstirred for 16 hrs, before being washed with 3M HCl solution (2×10 mL)and water (2×10 mL). The combined aqueous phases were re-extracted withDCM (10 mL), then the combined organic layers were dried (Na₂SO₄) andconcentrated under vacuum. The residue was recrystallized (EtOH/water)and further purification carried out by chromatography on silica(eluent: 10% MeOH in DCM) to affordN-(4-hydroxypyridin-3-yl)benzenesulfonamide (7 mg, 3%).

Example 3N-(4-hydroxypyridin-3-yl)-4-(trifluoromethyl)benzene-1-sulfonamide

A mixture of 3-amino-pyridin-4-ol (100 mg, 0.908 mmol) and4-trifluoromethyl)-benzene-1-sulfonyl chloride (222 mg, 0.908 mmol) washeated at 120° C. for 2 hrs under nitrogen. The cooled residue waspartitioned between water and EtOAc and the organic phase was washedwith a saturated solution of NaHCO₃ (5 mL) followed by brine (5 mL). Itwas then dried (MgSO₄), the mixture was filtered and the filtrateconcentrated in vacuo. Purification was carried out by automatedpreparative HPLC (low pH method) to affordN-(4-hydroxypyridin-3-yl)-4-(trifluoromethyl)benzene-1-sulfonamide as apink solid (22 mg, 8%).

Example 4N-(4-hydroxypyridin-3-yl)-4-(trifluoromethoxy)benzene-1-sulfonamide

The procedure to prepareN-(4-hydroxypyridin-3-yl)-4-(trifluoromethyl)benzene-1-sulfonamide wasused except that 4-(trifluoromethoxy)benzene-1-sulfonyl chloride wasused instead of 4-trifluoromethyl)-benzene-1-sulfonyl chloride (14%).

Example 5 N-(5-chloro-3-hydroxypyridin-2-yl)-1-phenylmethanesulfonamide

To a solution of 2-amino-5-chloro-3-methoxypyridine (100 mg, 0.631mmol), prepared according to literature (Int. Appl. WO 2011085126) inpyridine (0.5 mL) benzyl sulfonyl chloride (120 mg, 0.631 mmol) wasadded and the solution was stirred at 50° C. for 1 h. The pyridine wasevaporated, DCM was added (10 mL) followed by a solution of 1M BBr₃ inDCM dropwise (0.95 mL, 0.95 mmol). After 1 hr the mixture was quenchedwith 5M NaHCO₃ (10 mL), and more DCM was added (30 mL). The phases wereseparated and the organic phase was washed with brine (2 mL), dried(Na₂SO₄), the mixture was filtered and the filtrate evaporated todryness to afford an orange oil which was chromatographed on silica(eluent: heptane:EtOAc 1:1) to afford the product as an off-white solid.Further purification was achieved by slurrying the solid in DCM/heptane1:5 (5 mL) followed by filtration (66 mg, 35%).

Example 6N-(5-chloro-3-hydroxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyridine-3-sulfonamide

A solution of6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide (100mg, 0.299 mmol) in pyrrolidine (1 mL) was heated at 80° C. for 2 hrs.The pyrrolidine was evaporated and DCM was added (3 mL). 1M BBr₃ in DCM(3 mL, 3 mmol) was then added and the mixture was stirred for 3 hrsbefore being made alkaline with saturated NaHCO₃. The phases wereseparated and the organic phase was washed with brine (2 mL), dried(Na₂SO₄), the mixture was filtered and the filtrate evaporated todryness to afford a dark blue oil which was subjected to automatedreverse phase HPLC (low pH method) to affordN-(5-chloro-3-hydroxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyridine-3-sulfonamideas the formate salt (29 mg, 27%).

Example 7 N-(5-chloro-3-hydroxypyridin-2-yl) pyridine-3-sulfonamide

To a solution of 5-chloro-3-methoxypyridin-2-amine (100 mg, 0.631 mmol)in pyridine (1 mL) pyridine-3-sulfonyl chloride hydrochloride (135 mg,0.631 mmol) was added and the solution was stirred at room temperaturefor 1 hr. The pyridine was evaporated, DCM was added (5 mL) followed by1M BBr₃ in DCM (0.95 mL, 0.95 mmol) and the solution was stirredovernight. Saturated NaHCO₃ (5 mL) and more DCM (30 mL) were added. Thephases were separated and the organic phase was washed with brine (2mL), dried (Na₂SO₄), the mixture was filtered and the filtrateevaporated to dryness to afford an orange oil which was chromatographedon silica (eluent: heptane:EtOAc 2:1 then EtOAc:MeOH 9:1) to afford theproduct as a green oil. Further purification was achieved usingautomated reverse phase HPLC (high pH method) to affordN-(5-chloro-3-hydroxypyridin-2-yl) pyridine-3-sulfonamide as a brownsolid (29 mg, 16%).

Example 86-chloro-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide

6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide wasdeprotected with 1M BBr₃ in DCM and the resultant6-chloro-N-(5-chloro-3-hydroxypyridin-2-yl)-pyridine-3-sulfonamide waspurified as described in the procedure for the preparation ofN-(5-chloro-3-hydroxypyridin-2-yl) pyridine-3-sulfonamide, except thatHPLC using the low pH method was used, affording the formate salt (5%).

Example 9N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To a solution of 5-chloro-3-methoxypyridin-2-amine (167 mg, 0.821 mmol)in pyridine (3 mL) (3,5-dichlorophenyl)methanesulfonyl chloride (213 mg,0.821 mmol) was added and the mixture was stirred at room temperatureover 64 hrs. The solvent was evaporated and a rough purification wascarried out by silica chromatography (eluent: heptane:EtOAc 2:1).Product-containing fractions were combined, evaporated, dissolved in DCM(5 mL), then treated with 1M BBr₃ in DCM (0.82 mL, 0.82 mmol) and thesolution stirred for 3 hrs. The reaction was quenched with excesssaturated NaHCO₃ and more DCM added (15 mL). The phases were separatedand the organic phase was washed with brine (3 mL), dried (Na₂SO₄), themixture was filtered and the filtrate evaporated to dryness to afford apurple grey solid which was purified by slurrying in heptane:EtOAc toaffordN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamideas a white solid (55 mg, 18%).

Example 10N-(5-chloro-3-hydroxypyridin-2-yl)-6-[(propan-2-yl)amino]pyridine-3-sulfonamide

A solution of6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide (60mg, 0.180 mmol) in isopropylamine (1 mL) was heated at 145° C. in a CEMdiscover microwave for 4 hrs (about 50% conversion). The solvent wasevaporated and the residue was dissolved in DCM (5 mL), then treatedwith 1M BBr₃ in DCM (0.18 mL, 0.18 mmol) and the solution stirredovernight. The reaction was quenched with excess saturated NaHCO₃ andmore DCM was added (15 mL). The phases were separated and the organicphase was washed with brine (3 mL), dried (Na₂SO₄), the mixture wasfiltered and the filtrate evaporated to dryness to afford an orange oilwhich was purified by automated reverse phase HPLC (high pH method) toaffordN-(5-chloro-3-hydroxypyridin-2-yl)-6-[(propan-2-yl)amino]pyridine-3-sulfonamideas a brown oil (5 mg, 8%).

Example 115-bromo-6-chloro-N-[3-hydroxy-5-(propan-2-yl)pyridin-2-yl]pyridine-3-sulfonamide

To a solution of 3-methoxy-5-(propan-2-yl)pyridin-2-amine (117 mg, 0.549mmol) in pyridine (1 mL) was added 5-bromo-6-chloropyridine-3-sulfonylchloride (160 mg, 0.549 mmol) and the mixture was stirred for 1 hr atroom temperature. The solvent was evaporated and rudimentarypurification carried out by silica chromatography (eluent: heptane:EtOAc2:1). Product-containing fractions were combined, evaporated, dissolvedin DCM (5 mL), then treated with 1M BBr₃ in DCM (2.2 mL, 2.2 mmol) andthe solution stirred for 3 hrs. The reaction was quenched with excesssaturated NaHCO₃ and more DCM was added (15 mL). The phases wereseparated and the organic phase was washed with brine (3 mL), dried(Na₂SO₄), the mixture was filtered and the filtrate evaporated todryness to afford an orange oil which was purified by automated reversephase HPLC (high pH method) to afford5-bromo-6-chloro-N-[3-hydroxy-5-(propan-2-yl)pyridin-2-yl]pyridine-3-sulfonamideas a green solid (28 mg, 12%).

Example 12N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3-cyanophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (3-cyanophenyl)methanesulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride (18%).

Example 13(+/−)-5-bromo-6-chloro-N-[3-hydroxy-5-(1-hydroxypropan-2-yl)pyridin-2-yl]pyridine-3-sulfonamide

The procedure for preparation of5-bromo-6-chloro-N-[3-hydroxy-5-(propan-2-yl)-pyridin-2-yl]pyridine-3-sulfonamidewas used, except that(+/−)-2-(6-amino-5-methoxy-pyridin-3-yl)propan-1-ol was substituted for3-methoxy-5-(propan-2-yl)pyridin-2-amine (3%).

Example 145-bromo-6-chloro-N-(3-hydroxypyridin-2-yl)pyridine-3-sulfonamide

The procedure for preparation of5-bromo-6-chloro-N-[3-hydroxy-5-(propan-2-yl)pyridin-2-yl]pyridine-3-sulfonamidewas used, except that 2-amino-3-methoxy-pyridine was substituted for3-methoxy-5-(propan-2-yl)pyridin-2-amine. No chromatographicpurification of the intermediate methoxy ether was carried out (7%).

Example 15N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2,4-dichlorophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (2,4-dichlorophenyl)-methanesulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. Nochromatographic purification of the intermediate methoxy ether wascarried out and the target compound was purified by automated reversephase HPLC (low pH method) (18%).

Example 16N-(5-chloro-3-hydroxypyridin-2-yl)-1-(4-cyanophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (4-cyanophenyl)methanesulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. Nochromato-graphic purification of the intermediate methoxy ether wascarried out and the target compound was purified by automated reversephase HPLC (high pH method) (27%).

Example 17N-(5-chloro-3-hydroxypyridin-2-yl)-1-pyridin-3-ylmethanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that pyridin-3-ylmethanesulfonyl chloride,trifluoroacetate salt was substituted for(3,5-dichlorophenyl)methanesulfonyl chloride. No chromatographicpurification of the intermediate methoxy ether was carried out and thetarget compound was purified by automated reverse phase HPLC (low pHmethod) (7%).

Example 185-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyridine-3-sulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyridine-3-sulfonamidewas used except that5-bromo-6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamidewas substituted for6-chloro-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide. Inaddition, several ineffective attempts were made to purify theintermediate methoxy compound by chromatography (7%).

Example 19N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-difluorophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (3,5-difluorophenyl)methanesulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. Nochromato-graphic purification of the intermediate methoxy ether wascarried out and the target compound was purified by automated reversephase HPLC (high pH method) (14%).

Example 20N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2,5-dichlorothiophen-3-yl)methane-sulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (2,5-dichlorothiophen-3-yl)methane-sulfonylchloride was substituted for (3,5-dichlorophenyl)methanesulfonylchloride. No chromatographic purification of the intermediate methoxyether was carried out and the target compound was purified by automatedreverse phase HPLC (low pH method) (35%).

Example 21N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,4-dichlorophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (3,4-dichlorophenyl)methanesulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. An extracharge of sulfonyl chloride (0.3 mol equivalents) was added 16 hrs afterinitial addition and stirring continued for a further 30 min. Nochromatographic purification of the intermediate methoxy ether wascarried out and the target compound was purified by automated reversephase HPLC (low pH method) (17%).

Example 22N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3-chloro-5-fluorophenyl)methane-sulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (3-chloro-5-fluorophenyl)methane-sulfonyl chloridewas substituted for (3,5-dichlorophenyl)methanesulfonyl chloride. Anextra charge of sulfonyl chloride (0.3 mol equivalents) was added 16 hrsafter the initial addition and stirring continued for a further 30 min.No chromatographic purification of the intermediate methoxy ether wascarried out and the target compound was purified by automated reversephase HPLC (low pH method) (23%).

Example 231-(2,4-dichlorophenyl)-N-(4-hydroxypyridin-3-yl)methanesulfonamide

To a solution of 3-amino-4-methoxypyridine (120 mg, 0.754 mmol) inpyridine (3 mL) at 50° C. (2,4-dichlorophenyl)methanesulfonyl chloridewas added and the mixture was stirred for 2 hrs at this temperature. Thepyridine was evaporated, DCM (60 mL) was added followed by 1M HCl (20mL). The phases were separated and the organic phase was washed withbrine (20 mL), dried (Na₂SO₄), the mixture was filtered and the filtrateevaporated to dryness to afford a brown oil which was dissolved in DCM(10 mL) and 1M BBr₃ in DCM (2.26 mL, 2.26 mmol) was added. The mixturewas stirred for 1 hr before being quenched with excess saturated NaHCO₃.The phases were separated and the organic phase was washed with brine(20 mL), dried (Na₂SO₄), the mixture was filtered and the filtrateevaporated to dryness to afford a brown oil which was purified bypreparative automated reverse phase HPLC (low pH method) (6 mg, 2%).

Example 241-(3,5-dichlorophenyl)-N-(4-hydroxypyridin-3-yl)methanesulfonamide

The procedure for the preparation of1-(2,4-dichlorophenyl)-N-(4-hydroxypyridin-3-yl)methanesulfonamide wasused, except that (3,5-dichlorophenyl)methanesulfonyl chloride wassubstituted for (2,4-dichlorophenyl)methanesulfonyl chloride. HPLCpurification was carried out using the high pH method (1%).

Example 253,5-dichloro-N-(5-chloro-3-hydroxypyridin-2-yl)benzene-1-sulfonamide

To a solution of 2-amino-5-chloro-3-methoxypyridine (150 mg, 0.738 mmol)in pyridine (3 mL) at room temperature 3,5-dichlorobenzene-1-sulfonylchloride (181 mg, 0.738 mmol) was added and the mixture was stirred for2 hrs. The pyridine was evaporated, DCM (60 mL) was added followed by 1MHCl (20 mL). The phases were separated and the organic phase was washedwith brine (20 mL), dried (Na₂SO₄), the mixture was filtered and thefiltrate evaporated to dryness to afford a brown oil which was dissolvedin DCM (10 mL) and 1M BBr₃ in DCM (2.21 mL, 2.21 mmol) was added. Themixture was stirred for 1 hr before being quenched with saturatedNaHCO₃. The phases were separated and the organic phase was washed withbrine (20 mL), dried (Na₂SO₄), the mixture was filtered and the filtrateevaporated to dryness to afford a brown oil which was purified bypreparative automated reverse phase HPLC (low pH method) (120 mg, 46%).

Example 263,4-dichloro-N-(5-chloro-3-hydroxypyridin-2-yl)benzene-1-sulfonamide

The procedure for the preparation of3,5-dichloro-N-(5-chloro-3-hydroxypyridin-2-yl)-benzene-1-sulfonamidewas used, except that 3,4-dichlorobenzene-1-sulfonyl chloride wassubstituted for 3,5-dichlorobenzene-1-sulfonyl chloride (51%).

Example 27N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3-chlorophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (3-chlorophenyl)methanesulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. An extracharge of sulfonyl chloride (0.2 mol equivalents) was added 2 hrs afterinitial addition and stirring continued for a further 30 min. Nochromatographic purification of the intermediate methoxy ether wascarried out and the target compound was purified by automated reversephase HPLC (low pH method) (19%).

Example 28N-(5-chloro-3-hydroxypyridin-2-yl)-1-(4-chlorophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (4-chlorophenyl)methane-sulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. An extracharge of sulfonyl chloride (0.2 mol equivalents) was added 2 hrs afterinitial addition and stirring continued for a further 30 min. Nochromatographic purification of the intermediate methoxy ether wascarried out and the target compound was purified by automated reversephase HPLC (low pH method) (22%).

Example 29N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2-chlorophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (2-chlorophenyl)methane-sulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. An extracharge of sulfonyl chloride (0.2 mol equivalents) was added 2 hrs afterinitial addition and stirring continued for a further 30 min. Nochromatographic purification of the intermediate methoxy ether wascarried out and the target compound was purified by automated reversephase HPLC (low pH method) (33%).

Example 30N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2,5-dichlorophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (2,5-dichlorophenyl)methanesulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. An extracharge of sulfonyl chloride (0.2 mol equivalents) was added 2 hrs afterinitial addition and stirring continued for a further 30 min. Nochromatographic purification of the intermediate methoxy ether wascarried out and the target compound was purified by automated reversephase HPLC (low pH method) (36%).

Example 31N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,4-difluorophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (3,4-difluorophenyl)methanesulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. An extracharge of sulfonyl chloride (0.2 mol equivalents) was added 2 hrs afterinitial addition and stirring continued for a further 30 min. Nochromatographic purification of the intermediate methoxy ether wascarried out and the target compound was purified by automated reversephase HPLC (low pH method) (47%).

Example 321-(3,5-dichlorophenyl)-N-(3-hydroxy-5-methanesulfonylpyridin-2-yl)methane-sulfonamide

To a solution of 3-methoxy-5-(methylsulfanyl)pyridin-2-amine (191 mg,0.875 mmol) in pyridine (3 mL) was added(3,5-dichlorophenyl)methanesulfonyl chloride (227 mg, 0.875 mmol) andthe mixture was stirred for 1 hr. The solvent was evaporated and theresidue dissolved in DCM (25 mL), then treated with m-chloroperbenzoicacid (70% purity, 367 mg, 1.49 mmol) in three portions. After 15 min, 1MBBr₃ in DCM (2.62 mL, 2.62 mmol) was added and the solution stirred for3 hrs. The reaction was quenched with excess saturated NaHCO₃ and moreDCM was added (15 mL). The phases were separated and the organic phasewas washed with brine (3 mL), dried (Na₂SO₄), the mixture was filteredand the filtrate evaporated to dryness to afford a brown oil which waspurified by automated reverse-phase HPLC (low pH method) (17 mg, 5%).

Example 33N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3-chloro-5-cyanophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)-methanesulfonamidewas used except that (3-chloro-5-cyanophenyl)methanesulfonyl chloridewas substituted for (3,4-difluorophenyl)methanesulfonyl chloride and5-chloro-3-methoxypyridin-2-amine was substituted for6-chloro-4-methoxypyridazin-3-amine (21%).

Example 343-chloro-5-{[(5-chloro-3-hydroxypyridin-2-yl)sulfamoyl]methyl}benzamide

To a solution ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3-chlorocyanophenyl)-methanesulfonamide(35 mg, 0.098 mmol) in DMSO (1.5 mL) was added K₂CO₃ (14 mg, 0.098 mmol)and 27% H₂O₂ (aq, 36 μL, 0.293 mmol). The mixture was stirred for 3 hrsat 45° C. then purified by automated reverse phased HPLC (low pH method)to afford the title compound as a white solid (3 mg, 7%).

Example 351-(5-chloro-2-fluorophenyl)-N-(5-chloro-3-hydroxypyridin-2-yl)methane-sulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (5-chloro-2-fluorophenyl)methane-sulfonyl chloridewas substituted for (3,5-dichlorophenyl)methanesulfonyl chloride. Theintermediate methoxy ether was isolated by EtOAc/water workup andpurified by silica chromatography (eluent: DCM:MeOH 9:1). After theusual deprotection (5 equivalents of BBr₃ at 0° C.) and workup, thetarget compound was purified by automated reverse phase HPLC (low pHmethod) (26%).

Example 36N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To a solution of 6-chloro-4-methoxypyridazin-3-amine, prepared using aliterature procedure (WO2004108690A1) (403 mg, 1.97 mmol), in pyridine(3 mL) was added (3,5-dichlorophenyl)methanesulfonyl chloride (511 mg,1.97 mmol) and the mixture was stirred for 1 hr. The solvent wasevaporated and the residue dissolved in DCM (100 mL), then treated with1M BBr₃ in DCM (3.9 mL, 3.9 mmol) and the solution stirred 3 hrs. Afurther 2 mL of the BBr₃ solution was added with further stirring for 3hrs. The reaction was quenched with excess saturated NaHCO₃ and more DCMwas added (15 mL) A significant amount of solid precipitated, so themixture was filtered and the filtrate reserved. The solid was treatedwith 3M HCl until effervescence stopped and was carefully added back tothe DCM/NaHCO₃ mixture, ensuring the pH did not fall to below 7.

The phases were separated and the aqueous phase re-extracted with EtOAc(3×40 mL). The combined organic phases were dried (Na₂SO₄), the mixturewas filtered and the filtrate evaporated to dryness to afford brown oilwhich was purified by reverse-phase HPLC (low pH method). After removalof solvent the residue was slurried with hot EtOAc/Heptane (1:1, 5 mL)and filtered to affordN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamideas a tan solid (90 mg, 12%).

Example 37N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2,3-dichlorophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (2,3-dichlorophenyl)methanesulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. Theinitial reaction was complete in 1 hr. No chromatographic purificationof the intermediate methoxy ether was carried out and the targetcompound was purified by automated reverse phase HPLC (low pH method).

Example 38N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2,6-dichlorophenyl)methanesulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (2,6-dichlorophenyl)methanesulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride. Theinitial reaction was complete in 1 hr. No chromatographic purificationof the intermediate methoxy ether was carried out and the targetcompound was purified by automated reverse phase HPLC (low pH method)(34%).

Example 39 (a)(1R)—N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)ethane-1-sulfonamide,and (b)(1S)—N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)-ethane-1-sulfonamide

The procedure for preparation ofN-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichloro-phenyl)methanesulfonamidewas used except that (+/−)-1-(3,5-dichlorophenyl)ethane-1-sulfonylchloride was substituted for (3,5-dichlorophenyl)methanesulfonylchloride. The initial reaction was complete in 1 hr. No chromatographicpurification of the intermediate methoxy ether was carried out and theracemic mixture was purified by automated reverse phase HPLC (low pHmethod) (29%).

The racemate was resolved by SFC to afford separate enantiomers(1R)—N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)ethane-1-sulfonamideand(1S)—N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)ethane-1-sulfonamide,stereochemistry not assigned.

Example 405-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide

5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide (50 mg,0.13 mmol) was dissolved in DCM (2 mL) and the reaction mixture cooledto −10° C. followed by dropwise addition of BBr₃ (1.50 mL, 1.50 mmol) asa 1M DCM solution and stirring at room temperature for 16 hrs. Thereaction mixture was diluted with DCM (5 mL) and quenched with saturatedsodium bicarbonate. More DCM (10 mL) was added, the phases wereseparated and the organic phase washed with brine (2 mL), dried(Na₂SO₄), the mixture was filtered and the filtrate concentrated undervacuum and the residue purified by preparative TLC (eluent: 10% acetonein DCM) to afford5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide (5 mg,10%) as a brown solid.

Example 41N-(5-chloro-3-hydroxypyridin-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide wasused, except that 6-(trifluoromethyl)pyridine-3-sulfonyl chloride wassubstituted for5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide. Crudecompound was purified by preparative TLC (eluent: 30% MeOH in DCM) toaffordN-(5-chloro-3-hydroxypyridin-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide(30%) as an off-white solid.

Example 42N-(5-chloro-3-hydroxypyridin-2-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide wasused, except thatN-(5-chloro-3-methoxypyridin-2-yl)-3-(trifluoro-methoxy)benzene-1-sulfonamidewas substituted for5-bromo-N-(5-chloro-3-methoxy-pyridin-2-yl)pyridine-3-sulfonamide (yield44%, brown oil).

Example 43 N-(5-bromo-3-hydroxypyridin-2-yl)benzene sulfonamide

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfon-amide wasused, except that N-(5-bromo-3-methoxypyridin-2-yl)benzene sulfonamidewas substituted for5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide. Thecrude product was purified by preparative TLC (eluent: 2% MeOH in DCM)to afford N-(5-bromo-3-hydroxypyridin-2-yl)benzene sulfonamide (21%) asan off-white solid.

Example 44N-(5-bromo-3-hydroxypyridin-2-yl)-2,5-dichlorothiophene-3-sulfonamide

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfon-amide wasused, except thatN-(5-bromo-3-methoxypyridin-2-yl)-2,5-dichloro-thiophene-3-sulfonamidewas substituted for5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide. Thecrude product was purified by preparative TLC (eluent: 2% MeOH in DCM)to affordN-(5-bromo-3-hydroxypyridin-2-yl)-2,5-dichloro-thiophene-3-sulfonamide(24%) as an off-white solid.

Example 45N-(5-bromo-3-hydroxypyridin-2-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfon-amide wasused, except thatN-(5-bromo-3-methoxypyridin-2-yl)-3-(trifluoromethoxy)-benzene-1-sulfonamidewas substituted for5-bromo-N-(5-chloro-3-methoxy-pyridin-2-yl)pyridine-3-sulfonamide. Thecrude product was purified by preparative TLC eluting with 10% MeOH inDCM to affordN-(5-bromo-3-hydroxy-pyridin-2-yl)-3-(trifluoro-methoxy)benzene-1-sulfonamide(25%) as a brown oil.

Example 465-bromo-N-(5-bromo-3-hydroxypyridin-2-yl)-6-chloropyridine-3-sulfonamide

A solution of5-bromo-N-(5-bromo-3-methoxypyridin-2-yl)-6-chloropyridine-3-sulfon-amide(230 mg, 0.500 mmol) in DCM (2 mL) was cooled to 0° C. followed byaddition of neat BBr₃ (3850 μL, 24.5 mmol) drop wise. The reactionmixture was then stirred at room temperature for 16 hrs. The reactionmixture was diluted with 5 mL DCM and the reaction mixture brought to pH7-8 with sodium bicarbonate. More DCM (5 mL) was added, the phases wereseparated and the organic phase washed with brine (2 mL), dried(Na₂SO₄), the mixture was filtered and the filtrate concentrated undervacuum. The residue was chromatographed on silica (10% MeOH in DCM) toafford5-bromo-N-(5-bromo-3-hydroxypyridin-2-yl)-6-chloropyridine-3-sulfonamide(50 mg, 22%) as an off-white solid.

Example 47N-(5-bromo-3-hydroxypyridin-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide wasused, except thatN-(5-bromo-3-methoxypyridin-2-yl)-6-(trifluoro-methyl)pyridine-3-sulfonamidewas substituted for5-bromo-N-(5-chloro-3-methoxy-pyridin-2-yl)pyridine-3-sulfonamide. Thecrude product was purified by preparative TLC eluting with 10% MeOH inDCM to affordN-(5-bromo-3-hydroxy-pyridin-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide(16%) as an off-white solid.

Example 485-bromo-N-(5-bromo-3-hydroxypyridin-2-yl)-6-methoxypyridine-3-sulfonamide

To a solution of5-bromo-N-(5-bromo-3-hydroxypyridin-2-yl)-6-chloropyridine-3-sulfonamide(30 mg, 0.068 mmol) in MeOH (2 mL) sodium methoxide (183 mg, 3.38 mmol)was slowly added at room temperature and the reaction mixture wasstirred at room temperature for 16 hrs. It was then concentrated undervacuum and the residue dissolved in water (5 mL), with the pH adjustedto about 4 by addition of 1N HCl and extracted with ethyl acetate (2×10mL). The combined organic layers were dried (Na₂SO₄) and concentrated toafford the crude product which was purified by preparative TLC in 8%methanol in DCM to afford5-bromo-N-(5-bromo-3-hydroxypyridin-2-yl)-6-methoxypyridine-3-sulfonamide(5 mg, 17%) as a red solid.

Example 49N-(3-hydroxypyridin-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide wasused, except thatN-(3-methoxypyridin-2-yl)-6-(trifluoromethyl)-pyridine-3-sulfonamide wassubstituted for5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide. Thecrude product was purified by preparative TLC eluting with 20% MeOH inDCM to affordN-(3-hydroxypyridin-2-yl)-6-(trifluoromethyl)-pyridine-3-sulfonamide(2%) as a brown oil.

Example 50 Methyl 6-(2,5-dichlorothiophene-3-sulfonamido)-5-hydroxypyridine-3-carboxylate

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide wasused, except that methyl6-(2,5-dichlorothiophene-3-sulfonamido)-5-methoxypyridine-3-carboxylatewas substituted for5-bromo-N-(5-chloro-3-methoxy-pyridin-2-yl)pyridine-3-sulfonamide. Only3 equivalents of BBr₃ were added and the reaction time was 45 min. Thecrude product was chromatographed on silica (eluent: 30% EtOAc inhexanes) to afford methyl6-(2,5-dichlorothiophene-3-sulfonamido)-5-hydroxypyridine-3-carboxylate(34%) as an off-white solid.

Example 51 Methyl 6-benzenesulfonamido-5-hydroxypyridine-3-carboxylate

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide wasused, except that methyl6-benzenesulfonamido-5-methoxypyridine-3-carboxylate was substituted for5-bromo-N-(5-chloro-3-methoxypyridin-2-yl)pyridine-3-sulfonamide. Only 3equivalents of BBr₃ were added and reaction time was 45 min. The crudeproduct was chromatographed on silica (eluent: 30% EtOAc in hexanes) toafford methyl 6-benzenesulfonamido-5-hydroxypyridine-3-carboxylate (61%)as an off-white solid.

Example 524-bromo-3-fluoro-N-(4-hydroxypyridin-3-yl)benzene-1-sulfonamide

The procedure for preparation of5-chloro-N-(4-hydroxypyridin-3-yl)thiophene-2-sulfonamide was used,except that 4-bromo-3-fluorobenzene-1-sulfonyl chloride was substitutedfor 5-chlorothiophene-2-sulfonyl chloride A final purification wascarried out after preparative TLC using automated reverse-phase HPLC(low pH method) which afforded4-bromo-3-fluoro-N-(4-hydroxypyridin-3-yl)benzene-1-sulfonamide (68%) asa white solid.

Example 53N-(5-chloro-2-hydroxypyridin-3-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide wasused, except thatN-(5-chloro-2-methoxypyridin-3-yl)-3-(trifluoro-methoxy)benzene-1-sulfonamidewas substituted for5-bromo-N-(5-chloro-3-methoxy-pyridin-2-yl)pyridine-3-sulfonamide. Thecrude product was purified by preparative TLC eluting with 20% MeOH inDCM to affordN-(5-chloro-2-hydroxypyridin-3-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide(25%) as a brown oil.

Example 54N-(5-chloro-2-hydroxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

The procedure to prepare5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide wasused, except thatN-(5-chloro-2-methoxypyridin-3-yl)-6-(trifluoro-methyl)pyridine-3-sulfonamidewas substituted for5-bromo-N-(5-chloro-3-methoxy-pyridin-2-yl)pyridine-3-sulfonamide. Thecrude product was purified by silica chromatography eluting with 5% MeOHin DCM to affordN-(5-chloro-2-hydroxy-pyridin-3-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide(36%) as an off-white solid.

Example 555-bromo-N-(5-chloro-2-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide

To a solution of5-bromo-6-chloro-N-(5-chloro-2-hydroxypyridin-3-yl)pyridine-3-sulfonamide(50 mg, 0.13 mmol) in MeOH (2 mL) sodium methoxide (338 mg, 6.26 mmol)was added at room temperature and the reaction mixture was stirred atroom temperature for 16 hrs. The solvent was evaporated and the residuedissolved in water (5 mL), the pH adjusted to about 4 with 1N HCl andthe mixture extracted with ethyl acetate (2×10 mL). The combined organiclayers were dried (Na₂SO₄), the mixture was filtered and the filtrateconcentrated. The residue was purified by preparative TLC eluting with8% methanol in DCM to afford5-bromo-N-(5-chloro-2-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide(16 mg, 32%) as a white solid.

Example 562,5-dichloro-N-(5-chloro-3-hydroxypyridin-2-yl)thiophene-3-sulfonamide

To a solution of 2-amino-5-chloro-3-methoxypyridine (1.6 g, 10 mmol) inDCM (20 mL) pyridine (1.8 mL, 20.6 mmol) and2,5-dichlorothiophene-3-sulfonyl chloride (3.6 g, 12.7 mmol) were added.The mixture was stirred at room temperature for 64 h. The solvent wasevaporated and the residue was dissolved in hot EtOH. The mixture wasallowed to cool to room temperature. The intermediate product wascollected by filtration, dried in vacuum, suspended in DCM (60 mL), thentreated with 1M BBr₃ in DCM (33 mL, 33.0 mmol) and the solution stirredat room temperature for 18 h. The reaction was quenched with water andice and the resulting precipitate was collected by filtration, washedwith water and dried in vacuum to afford2,5-dichloro-N-(5-chloro-3-hydroxypyridin-2-yl)thiophene-3-sulfonamideas an off-white solid (1.4 g, 39%).

Example 57N-(5-chloro-4-hydroxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

A mixture of 3-amino-5-chloropyridin-4-ol (80 mg, 0.55 mmol) and6-trifluoromethyl-pyridine-3-sulfonyl chloride (136 mg, 0.55 mmol) washeated at 140° C. for 0.5 h. The mixture was allowed to cool to 60° C.and MeOH (2 drops) and acetone (2 mL) were added. The decanted solutionwas allowed to pass through an NH2-column, eluted with acetone and thenevaporated. The residue was chromatographed on silica(EtOAc/(MeOH/HOAc/H₂O 3:3:2) 40:1, 20:1, 10:1), evaporated, washed withwater and dried in vacuum to afford6-trifluoromethyl-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamide(2.1 mg, 1.1%).

Example 585-bromo-6-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamide

A mixture of 3-amino-5-chloropyridin-4-ol (65 mg, 0.45 mmol) and5-bromo-6-chloropyridine-3-sulfonyl chloride (131 mg, 0.45 mmol) wasmelted at 180° C. and then heated at 160° C. for 0.5 h. The mixture wasallowed to cool to 60° C. and MeOH (2 mL) was added. After stirring for0.5 h at 60° C. the precipitate was filtered off, washed with largevolumes of methanol and water and dried in vacuum to afford5-bromo-6-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamideas a grey solid (46 mg, 26%).

Example 595-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide

To a solution of5-bromo-6-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfon-amide(60 mg, 0.15 mmol) in MeOH (3 mL) NaOMe was added in portions until thesolution was saturated. The mixture was heated at 60° C. for 4 h andstirred at room temperature overnight. The mixture was evaporated andwater (5 mL) and MeOH (0.2 mL) were added. The mixture was acidifiedwith aqueous HCl and the precipitate was collected by filtration andwashed with methanol to afford5-bromo-6-methoxy-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamideas a brown-grey solid (45 mg, 76%).

Example 605-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamide

The procedure for preparation of5-bromo-6-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)-pyridine-3-sulfonamidewas used except that 5-bromopyridine-3-sulfonyl chloride was substitutedfor 5-bromo-6-chloro-pyridine-3-sulfonyl chloride.

Example 615-bromo-6-chloro-N-(4-hydroxypyridin-3-yl)pyridine-3-sulfonamide

A mixture of 3-amino-4-methoxypyridine (124 mg, 1.0 mmol) and5-bromo-6-chloro-pyridine-3-sulfonyl chloride (291 mg, 1.0 mmol) washeated at 130° C. for 2 h. 2M HCl in EtOH (200 μl) was added to the warmmixture to complete hydrolysis of the methoxy group and heated at 130°C. for one additional hour. The mixture was allowed to cool to 60° C.and MeOH (2 mL) was added. After stirring for 0.5 h at 60° C., thedecanted solution was allowed to pass through an NH₂-column, eluted withacetone/MeOH (1:0 to 1:1) and fractions containing product wereevaporated. The residue was chromatographed on silica(EtOAc/(MeOH/HOAc/H₂O 3:3:2) 40:1, 20:1, 10:1), evaporated and dried invacuum to afford5-bromo-6-chloro-N-(4-hydroxypyridin-3-yl)pyridine-3-sulfonamide (70 mg,19%).

Example 625-bromo-N-(4-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide

The procedure for preparation of5-bromo-6-methoxy-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamidewas used except that5-bromo-6-chloro-N-(4-hydroxypyridin-3-yl)pyridine-3-sulfonamide wassubstituted for5-bromo-6-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamide.

Example 63 2,5-dichloro-N-(4-hydroxypyridin-3-yl)thiophene-3-sulfonamide

A mixture of 3-amino-pyridin-4-ol (110 mg, 1.0 mmol) and2,5-dichlorothiophene-3-sulfonyl chloride (245 mg, 1.0 mmol) was heatedat 120° C. for 1.5 h. The mixture was allowed to cool to 60° C. and MeOH(2 mL) was added. After stirring for 0.5 h at 60° C., the decantedsolution was allowed to pass through a NH₂-column, eluted withacetone/MeOH (1:0 to 1:1) and fractions containing product wereevaporated. The residue was chromatographed on silica(EtOAc/(MeOH/HOAc/H₂O 3:3:2) 40:1, 20:1, 10:1), evaporated and dried invacuum to afford2,5-dichloro-N-(4-hydroxypyridin-3-yl)thiophene-3-sulfonamide (78 mg,25%).

Example 64N-(4-hydroxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

The procedure for preparation of2,5-dichloro-N-(4-hydroxypyridin-3-yl)thiophene-3-sulfonamide was usedexcept that 6-trifluoromethylpyridine-3-sulfonyl chloride wassubstituted for 2,5-dichlorothiophene-3-sulfonyl chloride.

Example 65 3,4-difluoro-N-(4-hydroxypyridin-3-yl)benzene-1-sulfonamide

The procedure for preparation of2,5-dichloro-N-(4-hydroxypyridin-3-yl)thiophene-3-sulfonamide was usedexcept that 3,4-difluorobenzene-1-sulfonyl chloride was substituted for2,5-dichlorothiophene-3-sulfonyl chloride.

Example 66 3,4-dichloro-N-(4-hydroxypyridin-3-yl)benzene-1-sulfonamide

The procedure for preparation of2,5-dichloro-N-(4-hydroxypyridin-3-yl)thiophene-3-sulfonamide was usedexcept that 3,4-dichlorobenzene-1-sulfonyl chloride was substituted for2,5-dichlorothiophene-3-sulfonyl chloride.

Example 67N-(2-hydroxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

The procedure for preparation of2,5-dichloro-N-(4-hydroxypyridin-3-yl)thiophene-3-sulfonamide was usedexcept that 6-trifluoromethylpyridine-3-sulfonyl chloride wassubstituted for 2,5-dichlorothiophene-3-sulfonyl chloride and3-amino-2-hydroxy-pyridine was substituted for 3-amino-pyridin-4-ol.

Example 685-bromo-6-chloro-N-(2-hydroxypyridin-3-yl)pyridine-3-sulfonamide

A mixture of 3-amino-2-hydroxypyridine (50 mg, 0.45 mmol) and5-bromo-6-chloro-pyridine-3-sulfonyl chloride (131 mg, 0.45 mmol) washeated at 120° C. for 1.5 h. The mixture was allowed to cool to 60° C.and MeOH (2 mL) was added. After stirring for 0.5 h at 60° C. the solidresidue was collected by filtration, boiled in hot MeOH (2 mL),filtrated, washed with water and dried in vacuum to afford5-bromo-6-chloro-N-(2-hydroxypyridin-3-yl)pyridine-3-sulfonamide (28 mg,17%).

Example 69 2,5-dichloro-N-(2-hydroxypyridin-3-yl)thiophene-3-sulfonamide

The procedure for preparation of5-bromo-6-chloro-N-(2-hydroxypyridin-3-yl)pyridine-3-sulfonamide wasused except that 3-amino-2-hydroxy-pyridine was substituted for3-amino-pyridin-4-ol.

Example 70N-(6-chloro-4-hydroxypyridin-3-yl)-1-(3,4-dichlorophenyl)methanesulfonamide

To a solution of 6-chloro-4-methoxypyridin-3-ylamine (0.95 mmol, 160 mg)in dichloromethane (1 mL) and pyridine (2 mmol, 165 microliter)(3,4-dichlorophenyl)-methanesulfonyl chloride ((275 mg, 0.95 mmol) wasadded and the mixture was stirred overnight and then concentrated on arotary evaporator. To the residue ethanol (99.5%, 5 mL) and NaOH (1 M, 2mL) were added and the mixture was heated at 60° C. until all materialwent into solution (took less than 5 min). The mixture was cooled, water(5 mL) and glacial acetic acid were added to pH 3-4 (checked with pHsticks). The precipitate was collected by filtration and dried to affordthe intermediateN-(6-chloro-4-methoxy-pyridin-3-yl)-3,4-dichlorophenyl-methanesulfon-amidewhich was dissolved in dichloromethane (2 mL), cooled on an ice-bath andboron tribromide (1M solution in dichloromethane, 2 mmol, 2 mL) wasadded dropwise. The mixture was stirred at room temperature overnight.The mixture was then partitioned between dichloromethane and aqueoussodium hydroxide at pH 13. The aqueous phase was collected, pH wasadjusted to approx. 3-4 with acetic acid and the mixture was extractedwith ethylacetate (20 mL). The organic phase was collected andevaporated and the residue was crystallized from methanol/water toafford the title compound (158 mg, 43%).

Example 715-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)-6-methoxypyridine-3-sulfonamide

5-chloro-3-methoxypyridin-2-ylamine (1 mmol) and5-bromo-6-chloropyridine-3-sulfonyl chloride (1 mmol) were meltedtogether at 130° C. for 3 hours. The mixture was cooled and partitionedbetween dichloromethane and aqueous sodium hydroxide at pH 13. Theaqueous phase was separated, and acetic acid was added to pH 3-4, andthen extracted with ethyl acetate. The organic phase was concentrated,heptane was added and the precipitate was collected to furnishN-(5-chloro-3-methoxypyridin-2-yl)-5-bromo-6-methoxypyridine-3-sulfonamide(90 mg). Subsequent treatment with boron tribromide was as described forthe preparation ofN-(6-chloro-4-hydroxypyridin-3-yl)-3,4-dichloro-phenyl-methanesulfonamideexcept for purifying the intermediateN-(5-chloro-3-hydroxypyridin-2-yl)-5-bromo-6-chloropyridine-3-sulfonamideby chromatography (SiO₂, ethyl acetate). This material was then stirredin a high pressure reaction vessel in 0.5 M NaOMe/MeOH (10 mL) at 80° C.for 4 hours. The mixture was cooled and evaporated and methanol (1 mL),water (1 mL) and acetic acid (0.5 mL) were added. The precipitate wascollected and dried to afford the title compound (90 mg, 22%).

Example 72 3,4-dichloro-N-(3-hydroxypyridin-4-yl)benzene-1-sulfonamide

3,4-dichlorobenzenesulfonyl chloride (1 mmol) and3-methoxypyridin-4-ylamine (1 mmol) were reacted without solvent at 130°C. for 4 hours, then cooled and dissolved in a mixture of NaOH (1 M, 10mL) and methanol (10 mL). Then water and dichloromethane were added andthe aqueous phase was collected. The aqueous phase was adjusted to pH3-4 with acetic acid and then extracted with ethyl acetate. The organicphase was evaporated and the residue was subjected to columnchromatography (SiO2, ethyl acetate) to giveN-(3-methoxypyridin-4-yl)-3,4-dichlorobenzenesulfonamide. The reactionof this intermediate with boron tribromide was as described forN-(6-chloro-4-hydroxypyridin-3-yl)-3,4-dichlorophenyl-methanesulfonamideexcept that a precipitate formed during the partition betweendichloromethane and aqueous sodium hydroxide at pH 13. Withoutseparating the phases, pH was adjusted to 3 with 1 M HCl and thetwo-phase mixture was filtered in order to collect the precipitate. Theprecipitate (30 mg, 9%) was the title compound according to nmr and massspectroscopy.

Example 732,5-dichloro-N-(6-chloro-4-hydroxypyridin-3-yl)thiophene-3-sulfonamide

Commercial 2-chloro-4-methoxy-5-nitropyridine (1.0 g) was hydrogenatedusing Raney nickel catalyst in THF until the consumption of hydrogenceased. The mixture was filtered and evaporated to give6-chloro-4-methoxypyridin-3-ylamine (813 mg). This amine (190 mg) wasreacted with 2,5-dichlorothiophene-3-sulfonyl chloride (259 mg)according to the procedure described forN-(6-chloro-4-hydroxypyridin-3-yl)-3,4-dichlorophenyl-methanesulfonamideexcept that after treatment with boron tribromide the mixture underwentchromatography (SiO2, EtOAc/MeOH/HOAc/water, 10:1:1:0.5) to afford thetitle compound (55 mg, 15%)

Example 742,5-dichloro-N-(5-chloro-2-hydroxypyridin-3-yl)thiophene-3-sulfonamide

5-Chloro-2-methoxypyridin-3-ylamine (10 mmol, 1.6 g) and2,5-dichlorothiophene-3-sulfonyl chloride (12 mmol, 3.2 g) were reactedaccording to the procedure forN-(6-chloro-4-hydroxypyridin-3-yl)-3,4-dichlorophenyl-methanesulfonamideto afford the title compound (1.02 g, 33%).

Example 75N-(5-bromo-3-hydroxypyrazin-2-yl)-1-(3,4-dichlorophenyl)methanesulfonamide

3,4-dichlorophenyl-methanesulfonyl chloride (2.4 mmol, 650 mg) was addedto a solution of 5-bromo-3-methoxypyrazine-2-ylamine (2 mmol, 410 mg)and pyridine (5 mmol, 411 microliter). The mixture was stirred for 72hours and then partitioned between ethyl acetate, water and acetic acid.The organic phase was collected and evaporated and the residue wascrystallized from ethyl acetate and heptane to afford the intermediateN-(5-bromo-3-methoxypyrazine-2-yl)-3,4-dichlorophenyl-methanesulfonamide(1.1 mmol, 470 mg). This was dissolved in dichloromethane (2 mL), cooledon an ice-bath, and boron tribromide (1 M solution in dichloromethane, 2mmol) was added. The mixture was stirred for 3 hours, then poured ontoNaHCO₃(s)/ice and stirred for additional 3 hours. The precipitate wascollected and dissolved in hot ethanol (99.5%), the mixture was filteredwhile hot, and water was added to the filtrate. The precipitate wascollected to afford the title compound (175 mg, 20%).

Example 76N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)methanesulfonamide

To a solution of 6-chloro-4-methoxypyridazin-3-amine (150 mg, 0.733mmol) in pyridine (4 mL) was added (3,4-difluorophenyl)methanesulfonylchloride (190 mg, 0.733 mmol) in 5 portions over 10 min and the mixturestirred for 1 hr. The pyridine was evaporated and the residue dissolvedin DCM (15 mL) and treated with 1M BBr₃ in DCM (0.733 mL, 0.733 mmol).Stirring was continued for 3 hrs at room temperature whereupon EtOAc wasadded (50 mL) and saturated NaHCO₃ (10 mL). The phases were separatedand the organic phase was washed with brine (20 mL), dried (Na₂SO₄), themixture filtered and the filtrate evaporated to dryness to afford abrown oil which was purified by automated reverse phase HPLC (low pHmethod) to afford the title compound as a tan solid (17 mg, 7%).

Example 771-(3,5-dichlorophenyl)-N-[3-hydroxy-5-(propane-2-sulfonyl)pyridin-2-yl]methanesulfonamide

To a stirred solution of1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)pyridin-2-yl]methanesulfonamide(100 mg, 0.22 mmol) in CHCl₃ (10 mL) under nitrogen was added neat borontribromide (166 mg, 0.662 mmol) at 0° C. The reaction mixture wasallowed to warm to room temperature and stirred 16 h. The mixture wasdiluted with more chloroform and quenched with water. The aqueous layerwas brought to pH 7 by the addition of saturated NaHCO₃ and extractedwith more CHCl₃ followed by EtOAc. The combined organic layers wereconcentrated to obtain a crude residue which was purified by flashsilica chromatography (eluent 1.5% MeOH:DCM). Further purification wasachieved by crystallisation from a mixture of CHCl₃, MeOH and pentanefollowed by automated reverse phase HPLC (high pH method) to afford thetitle compound as an off white solid (55 mg, 57%).

Example 78N-(5-chloro-3-hydroxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To 5-chloro-3-methoxypyrazin-2-amine (150 mg, 0.94 mmol) in pyridine:DCM1:1 (4 mL) at room temperature was added(3,5-dichlorophenyl)methanesulfonyl chloride (220 mg, 0.846 mmol) wasadded over 1 min. The mixture was stirred for 1 hr at this temperaturethen the pyridine was evaporated. The residue was dissolved in DCM (6mL) and 1M BBr₃ in DCM (1.5 mL, 1.5 mmol)) was added and the mixturestirred for 2 hrs. Another 1.5 mL of BBr₃ in DCM was added and stirringcontinued for a further 1 hr. The reaction was quenched carefully withwater, EtOAc was added and the phases separated. The EtOAc layer wasevaporated and the residue was purified by automated preparative HPLC(low pH method) to afford the title compound as a white solid. Furtherpurification was achieved by recrystallisation from MeOH (51 mg, 15%).

Example 795-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-phenoxypyridine-3-sulfonamide

To a stirred solution of phenol (24 mg, 0.25 mmol) in DMF (1 mL) at roomtemperature was added sodium hydride (29 mg, 1.2 mmol) and stirred for 5min. To this was added a solution of5-bromo-6-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-2-sulfonamide(50 mg, 0.13 mmol) in DMF (1 mL) and the reaction was heated using aBiotage microwave for 40 mins at 150° C. The mixture was acidified to pH5 (0.2M HCl) and extracted with EtOAc (3×10 mL). The organics werecombined and washed with brine (2×10 mL), dried (MgSO₄), the mixturefiltered and the filtrate concentrated to dryness to yield purple oilwhich was purified by automated reverse phase HPLC (high pH method).

Further purification was achieved by trituration with heptane to yieldthe title compound as an off-white solid (7 mg, 12%).

Example 80N-(5-bromo-3-hydroxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)-methanesulfonamidewas used except that 5-bromo-3-methoxypyrazin-2-amine was substitutedfor 5-chloro-3-methoxypyrazin-2-amine and(3,5-dichlorophenyl)methane-sulfonyl chloride was substituted for(3,4-difluorophenyl)methanesulfonyl chloride (25%).

Example 81N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2,4-dichlorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)-methanesulfonamidewas used except that (2,4-dichlorophenyl)methanesulfonyl chloride wassubstituted for (3,4-difluorophenyl)methanesulfonyl chloride (5%).

Example 821-(3,5-dichlorophenyl)-N-(4-hydroxy-6-iodopyridazin-3-yl)methanesulfonamide

and

Example 83N-(6-bromo-4-hydroxypyridazin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To a stirred solution of (6-bromo-4-methoxypyridazin-3-amine and6-iodo-4-methoxy-pyridazin-3-amine (0.8 g, mixture not separated inprevious step, estimated 3.92 mmol) in pyridine (9 mL) was added(3,5-dichlorophenyl)methanesulfonyl chloride (1.02 g, 3.92 mmol) at roomtemperature and the mixture stirred for 16 hrs. Water was then added andthe mixture extracted with EtOAc (3×150 mL). The combined organic layerswere washed with more water and brine, then concentrated and purified byflash silica chromatography (eluent: 1% MeOH:DCM) to afford a mixture ofmethoxy ethers (250 mg).

To this mixture in DCM (5 mL) was added neat boron tribromide (166 μl,1.76 mmol) and the mixture stirred for 3 h before being diluted with DCMand neutralised with saturated NaHCO₃ (pH 7). The phases were separatedand the aqueous phase extracted with DCM and EtOAc. The combined organiclayers were dried (MgSO₄), the mixture filtered and the filtrateconcentrated to dryness to yield an oil which was purified by automatedreverse phase HPLC (low pH method) to afford1-(3,5-dichlorophenyl)-N-(4-hydroxy-6-iodopyridazin-3-yl)methanesulfonamide(22 mg, 16%) andN-(6-bromo-4-hydroxypyridazin-3-yl)-1-(3,5)-dichlorophenyl)methanesulfonamide(22 mg, 18%).

Example 843-bromo-N-(5-bromo-4-hydroxypyridin-3-yl)-4-methoxybenzene-1-sulfonamide

To a stirred solution of 3-amino-5-bromopyridin-4-ol (200 mg, 1.06 mmol)in pyridine (15 mL) at 80° C. was added DMAP (5 mg, 0.04 mmol) followedby 4-bromo-3-methoxy-benzene-1-sulfonyl chloride (302 mg, 1.06 mmol) andthe mixture stirred for 1 hr at 80° C. The reaction mixture wasconcentrated in vacuo, partitioned between EtOAc (60 mL) and water (40mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuoto afford a brown solid which was purified by automated reverse phaseHPLC (low pH method) to afford the title compound as an off-white solid(50 mg, 10%).

Example 85N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methane-sulfonamide

To a stirring solution ofN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(649 mg, 1.74 mmol) in DCM (60 mL) was added BBr₃ (0.68 mL, 6.96 mmol)and the mixture stirred 30 mins. The reaction mixture was periodicallyre-treated with the same amount of BBr₃ over a 6 hr period untilstarting material had been fully converted (as judged by LCMS). Thereaction mixture was quenched with water (30 mL), the layers wereseparated, the aqueous layer was extracted with DCM (2×60 mL), allorganic layers were combined and were concentrated in vacuo to afford ayellow solid which was purified by automated reverse phase HPLC (low pHmethod) to afford the title compound as an off white solid (62 mg, 10%).

Example 86N-(5-chloro-4-hydroxypyridin-3-yl)-6-phenoxypyridine-3-sulfonamide

To a stirring solution of 3-amino-5-chloropyridin-4-ol (250 mg, 1.73mmol) in pyridine (3 mL) was added DMAP (10 mg, 0.08 mmol) and6-phenoxypyridine-3-sulfonyl chloride (466 mg, 1.73 mmol). The reactionwas left stirring at 40° C. under nitrogen for 3 hr. The reactionmixture was concentrated in vacuo, diluted with EtOAc (60 mL), washedtwice with water (40 mL) and washed with saturated brine (40 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to afforda purple solid which was purified by automated reverse phase HPLC (lowpH method) to afford the title compound as an off white solid (48 mg,7%).

Example 87N-(6-chloro-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)-methanesulfonamidewas used except 6-chloro-4-methoxypyridin-3-amine was substituted for6-chloro-4-methoxypyridazin-3-amine and(3,5-dichlorophenyl)methane-sulfonyl chloride was substituted for(3,4-difluorophenyl)methanesulfonyl chloride (11%).

Example 881-(3-chlorophenyl)-N-[5-(ethanesulfonyl)-3-hydroxypyrazin-2-yl]methane-sulfonamide

To a solution of1-(3-chlorophenyl)-N-[5-(ethanesulfonyl)-3-methoxypyrazin-2-yl]-methanesulfonamide(330 mg, 0.660 mmol) in DCM (12 mL) was added BBr₃ (1M in DCM, 1.98 mL,1.98 mmol) and the solution stirred 3 hrs, then quenched by the additionof water (8 mL) and more DCM (50 mL) was added. The phases wereseparated and the organic phase was washed with brine (5 mL), dried(Na₂SO₄), the mixture filtered and the filtrate evaporated to dryness toafford a red oil which was purified by automated reverse-phase HPLC(high pH method) to afford the title compound as a white solid (28 mg,11%).

Example 893,5-dichloro-N-(5-chloro-4-hydroxypyridin-3-yl)benzene-1-sulfonamide

To a stirred solution of 3-amino-5-chloropyridin-4-ol (150 mg, 1.04mmol) and N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol) in pyridine (3mL) at 0° C. was added 3,5-dichlorobenzene-1-sulfonyl chloride (255 mg,1.04 mmol) and the mixture was stirred at room temperature for 2 hrs.The pyridine was evaporated under reduced pressure, the residuere-dissolved in water (10 mL), extracted with EtOAc (4×10 mL), thecombined organics washed with brine (3×5 mL), dried (MgSO₄), filteredand concentrated to yield a crude purple solid which was purified byautomated reverse-phase HPLC (high pH method) to afford the titlecompound as a white solid (19 mg, 5%).

Example 90N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chlorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)-methanesulfonamidewas used except that 2-chlorophenyl)methanesulfonyl chloride wassubstituted for (3,4-difluorophenyl)methanesulfonyl chloride (11%yield).

Example 915-bromo-N-(5-bromo-4-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide

To a solution of 3-amino-5-bromopyridin-4-ol (250 mg, 0.926 mmol) inpyridine (3 mL) at 80° C. was added a crystal of DMAP, and the solutionstirred at this temperature for 10 min. Then5-bromo-6-chloropyridine-3-sulfonyl chloride (269 mg, 0.926 mmol) wasadded in portions over 3 min. The mixture was stirred for 1 hr at thistemperature then the pyridine was evaporated. The residue was suspendedin MeOH (10 mL), methanolic sodium methoxide solution added via syringe(5.4M, 1.2 mL, 6.5 mmol) and the mixture heated at 75° C. for 3 h. Thesolvent was evaporated and the residue acidified with 0.5M HCl. EtOAc(50 mL) was added, the phases were separated and the organic phase waswashed with brine (20 mL), dried (Na₂SO₄), the mixture filtered and thefiltrate evaporated to dryness to afford a red solid which was purifiedby automated reverse-phase HPLC (low pH method) to afford the titlecompound as a pink solid (10 mg, 2%).

Example 92N-(6-bromo-5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)methane-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(6-bromo-5-chloro-3-methoxy-pyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(14%).

Example 931-(2-chlorophenyl)-N-(4-hydroxy-6-methanesulfonylpyridazin-3-yl)methane-sulfonamide

The procedure to prepare1-(3-chlorophenyl)-N-[5-(ethanesulfonyl)-3-hydroxypyrazin-2-yl]methanesulfonamidewas used except that1-(2-chlorophenyl)-N-(6-methanesulfonyl-4-methoxypyridazin-3-yl)methanesulfonamidewas substituted for1-(3-chlorophenyl)-N-[5-(ethanesulfonyl)-3-methoxypyrazin-2-yl]methanesulfonamide.Further purification was achieved after HPLC with a DCM/heptanerecrystallisation (21%).

Example 94N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3-chloro-5-fluorophenyl)methane-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)-methanesulfonamidewas used except that (3-chloro-5-fluorophenyl)methanesulfonyl chloridewas substituted for (3,4-difluorophenyl)methanesulfonyl chloride (14%).

Example 953,5-dichloro-N-(6-chloro-4-hydroxypyridazin-3-yl)benzene-1-sulfonamide

To a solution of 6-chloro-4-methoxypyridazin-3-amine (250 mg, 1.22 mmol)in pyridine (3 mL), pre-heated to 80° C. was added 3,5-dichlorobenzenesulfonyl chloride (300 mg, 1.22 mmol) and the mixture stirred at thistemperature for 2 hrs. The pyridine was evaporated and the residuechromatographed on silica (eluent: heptane:EtOAc 1:2). Productcontaining fractions were combined, the solvent evaporated and dissolvedin DCM (15 mL). 1M BBr₃ in DCM (2.00 mL, 2.00 mmol) was added and thesolution stirred 1 hr, before being quenched with saturated NaHCO₃ (10mL). The phases were separated and the organic phase was washed withbrine (3 mL), dried (Na₂SO₄), the mixture filtered and the filtrateevaporated to dryness to afford a yellow oil which was purified byautomated reverse phase HPLC (low pH method) to afford the titlecompound as an off-white solid (36 mg, 8%).

Example 96N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3-chlorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)-methanesulfonamidewas used except that (3-chlorophenyl)methanesulfonyl chloride wassubstituted for (3,4-difluorophenyl)methanesulfonyl chloride (18%).

Example 97N-(5-bromo-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To 3-amino-5-bromopyridin-4-ol (250 mg, 1.32 mmol) in pyridine (3 mL) at80° C. was added a crystal of DMAP then(3,5-dichlorophenyl)methanesulfonyl chloride was added in portions over3 min. The mixture was stirred for 1 hr at this temperature then thepyridine was evaporated. The residue was dissolved in DMSO andprecipitated by addition of MeOH. The mixture was filtered and the solidwashed with MeOH followed by water and dried in air to afford the titlecompound as a white solid (82 mg, 15%).

Example 983-[(5-chloro-4-hydroxypyridin-3-yl)sulfamoyl]-N,N-diethylbenzamide

To a stirred solution of3-[(5-chloro-4-hydroxypyridin-3-yl)sulfamoyl]benzoic acid (54 mg, 0.15mmol) in DMF (3 mL), HATU (83 mg, 0.22 mmol) and DIPEA (0.08 mL, 0.44mmol) were added and left to stir for 30 mins at room temperature undernitrogen. Diethylamine (0.03 mL, 0.29 mmol) was added to the reactionmixture, the reaction was left stirring and under a nitrogen atmospherefor 15 hrs.

The reaction mixture was concentrated in vacuo (with addition of heptane(2 mL) to aid DMF evaporation) affording a viscous brown mixture. Thiswas purified by automated reverse phase HPLC (low pH method) to affordthe title compound as a pale pink solid (37 mg, 65%).

Example 991-(3,4-difluorophenyl)-N-(4-hydroxy-6-methanesulfonylpyridazin-3-yl)methane-sulfonamide

1M BBr₃ in DCM (583 μL, 0.583 mmol) was added dropwise under nitrogen toa stirring solution of1-(3,4-difluorophenyl)-N-(6-methanesulfonyl-4-methoxypyridazin-3-yl)-methanesulfonamide(30% pure, 85 mg, 0.06 mmol) in DCM (2 mL). The reaction was stirred for1 hr then concentrated in vacuo. The residue was purified by flashcolumn chromatography over silica (Biotage 10 g SNAP cartridge) elutingwith DCM:MeOH gradient 1:0 to 8.5:2.5 to the title compound as a whitesolid (16 mg, 62%).

Example 1003-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)-4-methylbenzene-1-sulfonamide

The procedure to prepare3,5-dichloro-N-(5-chloro-4-hydroxypyridin-3-yl)benzene-1-sulfonamide wasused, except that 3-chloro-4-methylbenzene-1-sulfonyl chloride wassubstituted for 3,5-dichlorobenzene-1-sulfonyl chloride, no DMAP wasused and the temperature was 60° C. (8%).

Example 1015-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-(propan-2-yloxy)pyridine-3-sulfonamide

To a stirred solution of propan-2-ol (1 mL, 13.1 mmol) in DMF (1 mL) atroom temperature was added sodium hydride (29 mg, 1.2 mmol) and stirredfor 5 mins. To this was added a solution of5-bromo-6-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-2-sulfonamide(50 mg, 0.13 mmol) in DMF (1 mL) and the reaction mixture heated using aBiotage microwave for 40 mins at 150° C. then acidified to pH5 (0.2MHCl) and extracted with EtOAc (3×10 mL). Organics were combined andwashed with brine (2×10 mL), dried (MgSO4), filtered and concentrated todryness to yield a deep purple oil which was purified by automatedreverse phase HPLC (high pH method) to yield the title compound as anoff white solid (7 mg, 12%).

Example 1023-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)-4-(trifluoromethoxy)benzene-1-sulfonamide

The procedure to prepare3,5-dichloro-N-(5-chloro-4-hydroxypyridin-3-yl)benzene-1-sulfonamide wasused, except that 3-chloro-4-(trifluoromethoxy)benzene-1-sulfonylchloride was substituted for 3,5-dichlorobenzene-1-sulfonyl chloride, noDMAP was used and the temperature was 60° C. Further purification wasachieved by re-crystallisation from MeOH/water (5%).

Example 103N-(5-cyano-3-hydroxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(5-cyano-3-methoxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxy-pyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(9%).

Example 1041-(3,5-dichlorophenyl)-N-[4-hydroxy-6-(propane-1-sulfonyl)pyridazin-3-yl]methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propane-1-sulfonyl)pyridazin-3-yl]methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(9%).

Example 105N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dimethoxyphenyl)methanesulfonamide

To a stirred solution ofN-[5-chloro-3-(prop-2-en-1-yloxy)pyridin-2-yl]-1-(3,5-dimethoxyphenyl)methanesulfonamide(30 mg, 0.08 mmol) in MeOH (1 mL) was addedbis[3-(diphenylphosphinyl)cyclopenta-2,4-dien-1-yl]iron;dichloromethane; dichloropalladium (61 mg, 0.08 mmol) at roomtemperature. After 10 min K₂CO₃ (32 mg, 0.23 mmol) was added and thereaction mixture was stirred at room temperature for 3.5 hrs. The cooledreaction mixture was filtered and the filtrate was concentrated. Theresidue was purified by preparative TLC (eluent 7:30 MeOH:DCM) to affordthe title compound as a brown solid (8 mg, 30%).

Example 1065-chloro-N-(5-chloro-3-hydroxypyridin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that5-chloro-N-(5-chloro-3-methoxy-pyridin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(28%).

Example 107N-(2-chloro-4-hydroxypyrimidin-5-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

1M BBr₃ in DCM (575 μL, 0.575 mmol) was added to a stirring solution ofN-(2-chloro-4-methoxypyrimidin-5-yl)-1-(3,5-dichlorophenyl)methanesulfonamide(55 mg, 0.14 mmol) in DCM (2 mL) under nitrogen. The reaction wasstirred at room temperature for 2 hrs then partitioned between DCM (15mL) and saturated aq. NaHCO₃ (15 mL). The aqueous was re-extracted withDCM (15 mL). The aqueous phase was then brought to pH ˜2 by the carefuladdition of concentrated HCl. A white precipitate formed which wasisolated by filtration. The solid obtained was suspended in MeOH (1 mL),filtered and the filter pad was washed with DCM (2×1 mL), water (2×1mL), then dried in vacuo to afford the title compound (34 mg, 64%) as anoff white solid.

Example 1081-(3,5-dichlorophenyl)-N-[5-(ethanesulfonyl)-3-hydroxypyridin-2-yl]methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-[5-(ethane-sulfonyl)-3-methoxypyridin-2-yl]methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(22%).

Example 1093,4-dichloro-N-(6-chloro-4-hydroxypyridazin-3-yl)benzene-1-sulfonamide

The procedure to prepare3,5-dichloro-N-(6-chloro-4-hydroxypyridazin-3-yl)benzene-1-sulfonamidewas used except that 3,4-dichlorobenzene sulfonyl chloride wassubstituted for 3,5-dichlorobenzene sulfonyl chloride (5%).

Example 110N-(5-chloro-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To a stirred solution of 3-amino-5-chloropyridin-4-ol (150 mg, 1.04mmol) and N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol) in pyridine (3mL) at 0° C. was added (3,5-dichlorophenyl)methanesulfonyl chloride (135mg, 0.52 mmol) and the mixture stirred overnight. More sulfonyl chloride(67 mg, 0.26 mmol) was added to the reaction mixture and stirring wascontinued overnight. The mixture was acidified to pH3 with 1M HCl andextracted with EtOAc (3×15 mL). The organic layers contained substantialamounts of a pink solid so the mixture was filtered. The solid waswashed with HCl (1M) and dried in air to yield the title compound as apale pink solid (30 mg, 7%).

Example 1111-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-4-hydroxypyridazin-3-yl]methanesulfonamide

A stirred mixture of1-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-4-methoxypyridazin-3-yl]methanesulfonamide(400 mg, 0.91 mmol) in 1,4-Dioxane-HCl (10%) was kept at 90° C. for an3.5 hrs then concentrated in vacuo. The residue was treated with aqueousNaHCO₃ and extracted with EtOAc twice. The combined organic layers weredried (Na₂SO₄), filtered and the filtrate concentrated. The residue waspurified by silica chromatography followed by automated preparative HPLC(high pH method) to afford the title compound as a white solid (90 mg,23%).

Example 1121-(3,5-dichlorophenyl)-N-(3-hydroxy-5-methanesulfonylpyrazin-2-yl)methane-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-(5-methane-sulfonyl-3-methoxypyrazin-2-yl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(28%).

Example 1132,5-dichloro-N-(6-chloro-4-hydroxypyridazin-3-yl)thiophene-3-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that2,5-dichloro-N-(6-chloro-4-methoxy-pyridazin-3-yl)thiophene-3-sulfonamidewas substituted forN-(6-chloro-4-methoxy-pyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide.Purification was by silica chromatography (eluent: 1% MeOH in DCM)rather than HPLC (32%).

Example 1145-bromo-N-(6-chloro-4-hydroxypyridazin-3-yl)-6-methoxypyridine-3-sulfonamide

To a suspension of5-bromo-6-chloro-N-(6-chloro-4-hydroxypyridazin-3-yl)pyridine-3-sulfonamide(740 mg, 1.85 mmol) in MeOH (38 mL) was added sodium methoxide solution(5.4M in MeOH, 1.7 mL, 9.2 mmol) and the solution heated at 80° C. for 1hr. The solvent was evaporated, EtOAc added (80 mL) followed by 1M HCl(30 mL). A pink solid that did not dissolve in either was filtered offand then the solid was slurried with hot MeOH/water. Filtration anddrying in air yielded the title compound as a pink solid (450 mg, 61%).

Example 115N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2,3-dichlorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)-methanesulfonamidewas used except that (2,3-dichlorophenyl)methanesulfonyl chloride wassubstituted for (3,4-difluorophenyl)methanesulfonyl chloride (24%).

Example 116N-(6-chloro-4-hydroxypyridazin-3-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide

The procedure used to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamidewas used except thatN-(6-chloro-4-methoxy-pyridazin-3-yl)-3-(trifluoromethoxy)benzene-1-sulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide.Purification was by silica chromatography (eluent: 1-2% MeOH in DCM)rather than HPLC (28%).

Example 1176-(azetidin-1-yl)-5-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamide

To 3-amino-5-chloropyridin-4-ol (150 mg, 1.04 mmol) in pyridine (2 mL)in a sealable tube at 60° C. was added5-bromo-6-chloropyridine-3-sulfonyl chloride (272 mg, 0.934 mmol) inportions over 1 min. The mixture was stirred for 1 hr at thistemperature then the pyridine was evaporated and the residue dissolvedin DMSO (2 mL). Azetidine hydrochloride (291 mg, 3.11 mmol) and sodiumcarbonate (330 mg, 3.11 mmol) were added, the vessel sealed and themixture heated at 60° C. for 1 hr. The cooled reaction mixture wasdiluted with MeOH (4 mL), filtered and subjected to low pH preparativeHPLC. Product containing fractions were combined, the solvent evaporatedand the residue slurried with MeOH (4 mL) followed by filtration toafford the title compound as a pink solid (51 mg, 12%).

Example 1181-(3,5-dichlorophenyl)-N-[4-hydroxy-6-(propane-2-sulfonyl)pyridazin-3-yl]methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-4-hydroxy-pyridazin-3-yl]methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(propane-2-sulfonyl)pyridazin-3-yl]methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-4-methoxypyridazin-3-yl]methanesulfonamide (10%).

Example 1195-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-ethoxypyridine-3-sulfonamide

To a solution of5-bromo-6-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-2-sulfonamide(40 mg, 0.10 mmol) in DMF (1 mL) and EtOH (1 mL) was added NaH (14 mg,0.60 mmol) and the mixture heated at 150° C. for 40 mins in a Biotagemicrowave. The cooled reaction mixture was acidified to pH5 (0.2M HCl),extracted with EtOAc (3×10 mL), the organics combined and washed withbrine (2×10 mL), dried (MgSO4), filtered and concentrated under reducedpressure to afford a crude purple oil which was purified by automatedreverse phase HPLC to afford the title compound as an off white solid,(4.8 mg, 11%).

Example 1205-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that5-bromo-N-(5-chloro-3-methoxy-pyridin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(25%).

Example 121N-(6-chloro-4-hydroxypyridazin-3-yl)-3-cyanobenzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(6-chloro-4-methoxypyridazin-3-yl)-3-cyanobenzene-1-sulfonamide wassubstituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(31%).

Example 1223-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)-4-methoxybenzene-1-sulfonamide

The procedure to prepareN-(5-chloro-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)-methanesulfonamidewas used except that 3-chloro-4-methoxybenzene-1-sulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride (18%).

Example 1233-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-4-methoxybenzene-1-sulfonamide

The procedure to prepareN-(5-chloro-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)-methanesulfonamidewas used except that 3-bromo-4-methoxybenzene-1-sulfonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride (32%).

Example 1241-(3,5-dichlorophenyl)-N-[3-hydroxy-5-(propane-1-sulfonyl)pyridin-2-yl]methanesulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[3-hydroxy-5-(propane-2-sulfonyl)-pyridin-2-yl]methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-1-sulfonyl)pyridin-2-yl]methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-[3-methoxy-5-(propane-2-sulfonyl)pyridin-2-yl]methane-sulfonamide(34%).

Example 125N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-dichlorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)-methanesulfonamidewas used except that (3,4-dichlorophenyl)methanesulfonyl was substitutedfor (3,4-difluorophenyl)methanesulfonyl chloride (7%).

Example 1261-(3,5-dichlorophenyl)-N-(4-hydroxy-6-methanesulfonylpyridazin-3-yl)methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-4-hydroxy-pyridazin-3-yl]methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-(6-methanesulfonyl-4-methoxypyridazin-3-yl)methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-(6-ethanesulfonyl-4-methoxypyridazin-3-yl)methanesulfonamide.Purification was by prep TLC (eluent 7% MeOH in DCM, 12%).

Example 127N-(5-chloro-3-hydroxypyridin-2-yl)-1-(5-cyanothiophen-3-yl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(5-chloro-3-methoxypyridin-2-yl)-1-(5-cyanothiophen-3-yl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxy-pyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(24%).

Example 1285-bromo-6-chloro-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]pyridine-3-sulfonamide

To a stirred solution of 5-amino-2-(trifluoromethyl)pyridin-4-ol (130mg, 0.73 mmol) and N,N-dimethylpyridin-4-amine (4.4 mg, 0.036 mmol) inpyridine (1.5 mL) at 0° C. was added 5-bromo-6-chloropyridine-3-sulfonylchloride (220 mg, 0.759 mmol). The reaction mixture was stirred at roomtemperature for 1 hr. More 5-bromo-6-chloropyridine-3-sulfonyl chloride(26 mg, 0.091 mmol) was added and stirring continued for a further 1 hr.The pH was adjusted to 3 with 1M HCl, the mixture extracted with EtOAc(3×10 mL) and the organics combined, dried (MgSO₄), filtered and thefiltrate concentrated to dryness. The crude material was purified byautomated reverse phase HPLC (low pH method) to yield the title compoundas an off white solid (36 mg, 12%).

Example 1295-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-(piperidin-1-yl)pyridine-3-sulfonamide

To a solution of 3-amino-5-chloropyridin-4-ol (200 mg, 50% purity, 0.692mmol) in pyridine (2 mL) at 60° C. was added5-bromo-6-chloropyridine-3-sulfonyl chloride (201 mg, 0.692 mmol) inportions over 1 min. The mixture was stirred for 1 hr at thistemperature then the pyridine was evaporated and the purple oil treatedwith piperidine (2 mL) and the mixture refluxed 1 hr. The piperidine wasevaporated and the oil subjected to automated reverse phase prep. HPLC(low pH method) to afford the title compound as an off white solid (38mg, 12%).

Example 130N-(5-chloro-6-cyano-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)methane-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(5-chloro-6-cyano-3-methoxy-pyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(8%).

Example 131N-[5-(cyclopentanesulfonyl)-3-hydroxypyridin-2-yl]-1-(3,5-dichlorophenyl)methane-sulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-4-hydroxy-pyridazin-3-yl]methanesulfonamidewas used except thatN-[5-(cyclopentanesulfonyl)-3-methoxypyridin-2-yl]-1-(3,5-dichlorophenyl)methanesulfonamidewas substituted for1-(3,5-dichlorophenyl)-N-(6-ethanesulfonyl-4-methoxypyridazin-3-yl)methanesulfonamideand chloroform was used in place of DCM. Purification was achieved usingflash silica chromatography (eluent: 1.5% MeOH:DCM) and then byrecrystallisation from CHCl₃/MeOH/pentane (7%).

Example 132N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-6-methylpyridine-3-sulfonamide

To a stirred solution of 5-amino-2-(trifluoromethyl)pyridin-4-ol (150 mgat 50% purity, 0.421 mmol) in pyridine at 80° C. was added6-methylpyridine-3-sulfonyl chloride (prepared according to a methoddescribed in WO 2007/023186 A1), 55 mg, 0.29 mmol). The mixture wasstirred for 1 hr at this temperature then the pyridine was evaporated.The residue was purified by low pH automated preparative HPLC to affordthe title compound as a white solid (10 mg, 7%).

Example 1331-(3,5-dichlorophenyl)-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]methane-sulfonamide

The procedure to prepare5-bromo-6-chloro-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]pyridine-3-sulfonamidewas used except that 3,5-dichlorophenyl)methanesulfonyl chloride wassubstituted for 5-bromo-6-chloropyridine-3-sulfonyl chloride. HPLCpurification used the high pH method; (15%).

Example 134N-(5-chloro-3-hydroxy-6-methanesulfonylpyridin-2-yl)-1-(3,5-dichlorophenyl)-methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(5-chloro-6-methanesulfonyl-3-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide.Further purification was achieved by trituration with DCM (17%).

Example 1351-(3,4-dichlorophenyl)-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]methane-sulfonamide

The procedure to prepare5-bromo-6-chloro-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]pyridine-3-sulfonamidewas used except that (3,4-dichlorophenyl)methanesulfonyl chloride wassubstituted for 5-bromo-6-chloropyridine-3-sulfonyl chloride (12%).

Example 136N-(5-chloro-3-hydroxypyridin-2-yl)-6-(dimethylamino)-5-methanesulfonylpyridine-3-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(5-chloro-3-methoxypyridin-2-yl)-6-(dimethylamino)-5-methanesulfonylpyridine-3-sulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide.Purification was by silica chromatography (eluent EtOAc:hexane 1:1,20%).

Example 1375-bromo-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-6-methoxypyridine-3-sulfonamide

Sodium methoxide (5.4M, 0.1 mL, 0.54 mmol) was added to THF (3 mL) atroom temperature then5-bromo-6-chloro-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-pyridine-3-sulfonamide(30 mg, 0.069 mmol) was added and the reaction heated to 60° C. for 5hrs. The mixture was diluted with EtOAc (30 mL) and washed subsequentlywith water (10 mL) and brine (10 mL). The organic phase was dried overMgSO₄, filtered and concentrated in vacuo to give the title compound asan off white solid (16 mg, 54%).

Example 138N-(5-cyano-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To a solution ofN-(5-bromo-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methane-sulfonamide(390 mg, 0.94 mmol) in NMP (9 mL) was added copper(I) cyanide (422 mg,4.71 mmol) and the mixture heated at 175° C. for 5 hrs. The cooledreaction mixture was diluted with EtOAc (100 mL) and washed with brine(30 mL×4). The organic phase was dried (Na₂SO₄), filtered andconcentrated and the residue purified by automated reverse phase HPLC(high followed by low pH methods) to give the title compound as a pinksolid (82 mg, 24%).

Example 1391-(3,5-dichlorophenyl)-N-[4-hydroxy-6-(3-hydroxypropanesulfonyl)pyridazin-3-yl]methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that1-(3,5-dichlorophenyl)-N-[4-methoxy-6-(3-methoxypropanesulfonyl)pyridazin-3-yl]methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(6%).

Example 140N-[6-(cyclopentanesulfonyl)-4-hydroxypyridazin-3-yl]-1-(3,5-dichlorophenyl)-methanesulfonamide

The procedure to prepare1-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-4-hydroxy-pyridazin-3-yl]methanesulfonamidewas used except that N-[6-(cyclopentanesulfonyl)-4-methoxypyridazin-3-yl]-1-3,5-dichlorophenyl)methanesulfonamide was substituted for1-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-4-methoxypyridazin-3-yl]methane-sulfonamide(12%).

Example 141(+/−)-N-(5-bromo-3-hydroxypyrazin-2-yl)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-sulfonamide

1M BBr₃ in DCM (284 μL, 0.284 mmol) was added to a solution of(+/−)-N-(5-bromo-3-methoxypyrazin-2-yl)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-sulfonamide(20 mg, 0.03 mmol) in DCM (2 mL) under nitrogen. The reaction wasallowed to stir at room temperature for 2 hrs, then to stand for 48 hrs.The reaction was diluted with DCM (10 mL), washed with 1 N HCl (2×3 mL),brine (3 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography over silica (Biotage 10 g SNAP cartridge, eluting with agradient of heptane:EtOAc 1:1 to 0:1 then EtOAc:MeOH 1:0 to 9:1 toafford desired product as an off white solid. The product was suspendedin DCM (10 mL) and extracted into the aqueous phase by extracting with2M K₂CO₃ (3×3 mL). The combined extractions were washed with DCM (3×5mL) then brought to pH 1 by the addition of 3 N HCl. The aqueous phasewas then re-extracted with DCM (5×10 mL). The combined organicextractions were washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated in vacuo to afford the titlecompound (11 mg, 70%) as an off white solid.

Example 1423-[(5-bromo-3-hydroxypyrazin-2-yl)sulfamoyl]-N,N-diethylbenzamide

To a stirring solution of3-[(5-bromo-3-hydroxypyrazin-2-yl)sulfamoyl]benzoic acid (110 mg, 0.29mmol) in DMF (8 mL), HATU (168 mg, 0.44 mmol) and DIPEA (0.88 mL, 0.88mmol) was added and the mixture left to stir for 30 mins at 60° C. in asealed tube. Diethylamine (0.060 mL, 0.59 mmol) was added to thereaction mixture and the reaction was left stirring for 2 hrs at 60° C.The brown reaction mixture was concentrated in vacuo before beingdissolved in 1:1 DMSO: MeOH and being purified directly via automatedreverse phase HPLC to afford the title compound as an off-white solid(12 mg, 9%).

Example 143N-(2-chloro-5-hydroxypyrimidin-4-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(2-chloro-5-methoxy-pyrimidin-4-yl)-1-(3,5-dichlorophenyl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(24%).

Example 1443,4-dichloro-N-(2-chloro-5-hydroxypyrimidin-4-yl)benzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that3,4-dichloro-N-(2-chloro-5-methoxy-pyrimidin-4-yl)benzene-1-sulfonamidewas substituted forN-(6-chloro-4-methoxy-pyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(3%).

Example 1453,5-dichloro-N-(2-chloro-5-hydroxypyrimidin-4-yl)benzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that3,5-dichloro-N-(2-chloro-5-methoxy-pyrimidin-4-yl)benzene-1-sulfonamidewas substituted forN-(6-chloro-4-methoxy-pyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(44%).

Example 1463-[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]-N,N-diethylbenzamide

The procedure to prepare3-[(5-bromo-3-hydroxypyrazin-2-yl)sulfamoyl]-N,N-diethyl-benzamide wasused except that 3-[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]benzoicacid was substituted for3-[(5-bromo-3-hydroxypyrazin-2-yl)sulfamoyl]benzoic acid and heating ofthe second stage of the reaction was at 80° C. rather than 60° C. (42%).

Example 147N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(4-cyanophenyl)methanesulfonamide

To a stirred solution ofN-(6-chloro-4-methoxypyridazin-3-yl)-1-(4-cyanophenyl)-methanesulfonamide(274 mg, 0.81 mmol) in DCM (30 mL) was added 1M BBr₃ in DCM (3.24 mL,3.24 mmol) and the mixture left stirring for 3.5 hrs. The reactionmixture was quenched with water (20 mL), the layers were separated, theaqueous layer was extracted with DCM (2×30 mL), all organic layers werecombined and were concentrated in vacuo to a yellow solid which wasmostly starting material. The aqueous layer was further extracted withEtOAc (3×30 mL), the organic layers were combined and concentrated invacuo to afford 53 mg of a yellow solid which was also mostly startingmaterial.

The aqueous layer was filtered to obtain a white solid which wasdissolved in 1:1 DMSO:MeOH and purified via automated reverse phase HPLC(low pH method) to afford the title compound as a white solid (23 mg,9%).

Example 148N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(5-cyano-2-fluorophenyl)methane-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(6-chloro-4-methoxypyridazin-3-yl)-1-(5-cyano-2-fluorophenyl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(28%).

Example 149N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3-cyano-5-fluorophenyl)methane-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(6-chloro-4-methoxypyridazin-3-yl)-1-(3-cyano-5-fluorophenyl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(28%).

Example 1501-(2-chloro-5-cyanophenyl)-N-(2-chloro-5-hydroxypyrimidin-4-yl)methane-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas use except that1-(2-chloro-5-cyanophenyl)-N-(2-chloro-5-methoxypyrimidin-4-yl)methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(34%).

Example 1512-chloro-N-(6-chloro-4-hydroxypyridazin-3-yl)-4-cyanobenzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that2-chloro-N-(6-chloro-4-methoxy-pyridazin-3-yl)-4-cyanobenzene-1-sulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(10%).

Example 1523-chloro-N-(6-chloro-4-hydroxypyridazin-3-yl)-4-fluorobenzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that3-chloro-N-(6-chloro-4-methoxy-pyridazin-3-yl)-4-fluorobenzene-1-sulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(30%).

Example 1533,5-dichloro-N-(5-cyano-4-hydroxypyridin-3-yl)benzene-1-sulfonamide

To a solution ofN-(5-bromo-4-hydroxypyridin-3-yl)-3,5-dichlorobenzene-1-sulfonamide (367mg, 0.92 mmol) in NMP (9 mL) was added copper(I) cyanide (413 mg, 4.61mmol) and the mixture heated at 175° C. for 6 hrs. The cooled reactionmixture was diluted with EtOAc (100 mL) and washed with brine (30 mL×4).The organic phase was dried (Na₂SO₄), filtered and concentrated to givea brown residue which was triturated with MeOH. Further purification wasachieved by automated reverse phase HPLC (basic method) giving the titlecompound as a white solid (46 mg, 14%).

Example 1543-chloro-N-(6-chloro-4-hydroxypyridazin-3-yl)-5-fluorobenzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that3-chloro-N-(6-chloro-4-methoxy-pyridazin-3-yl)-5-fluorobenzene-1-sulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(29%).

Example 1553,5-dichloro-N-(4-hydroxy-6-methanesulfonylpyridin-3-yl)benzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that3,5-dichloro-N-(6-methanesulfonyl-4-methoxypyridin-3-yl)benzene-1-sulfonamidewas substituted for N-(6-chloro-4-methoxy-pyridazin-3-yl)-1-(2-chloro-5cyanophenyl)methanesulfonamide (35%).

Example 1563,5-dichloro-N-(6-chloro-4-hydroxypyridin-3-yl)benzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that3,5-dichloro-N-(6-chloro-4-methoxy-pyridin-3-yl)benzene-1-sulfonamidewas substituted forN-(6-chloro-4-methoxy-pyridazin-3-yl)-1-(2-chloro-5cyanophenyl)methanesulfonamideand HPLC was done using a neutral method (ammonium bicarbonate buffer asmobile phase) (7%).

Example 1571-(3,5-dichlorophenyl)-N-[5-hydroxy-2-(trifluoromethyl)pyrimidin-4-yl]methane-sulfonamide

To a stirring solution of1-(3,5-dichlorophenyl)-N-[5-methoxy-2-(trifluoromethyl)-pyrimidin-4-yl]methanesulfonamide(130 mg, 0.31 mmol) in DCM (15 mL) was added 1M BBr₃ in DCM (1.25 mL)was added and the mixture stirred for 5 hrs. Water was added slowly toquench the reaction and extracted with DCM (3×30 mL). Most of theproduct was in the aqueous phase which was re-extracted using EtOAc. TheEtOAc layer was dried (Na₂SO₄), filtered and concentrated in vacuo toyield the title compound as a white solid (80 mg, 64%).

Example 1583-chloro-5-fluoro-N-[5-hydroxy-2-(trifluoromethyl)pyrimidin-4-yl]benzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that3-chloro-5-fluoro-N-[5-methoxy-2-(trifluoromethyl)pyrimidin-4-yl]benzene-1-sulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(35%).

Example 1593,5-dichloro-N-(3-hydroxy-5-methanesulfonylpyrazin-2-yl)benzene-1-sulfonamide

To a stirred solution of3,5-dichloro-N-(5-methanesulfonyl-3-methoxypyrazin-2-yl)-benzene-1-sulfonamide(150 mg, 0.36 mmol) in DCM (25 mL) was added a solution of 1M BBr₃ inDCM (2.18 mL). On stirring a white precipitate formed. Additional DCM(25 ml) was added and the reaction was sonicated to get the solid backinto solution and stirring continued for a further 30 mins. The reactionwas quenched by the addition of sat NaHCO₃ (aq) until the reaction waspH 7. The reaction was re-acidified to pH 2 using 2M HCl and dilutedwith water (40 mL). A white precipitate that persisted throughout theadjustment of the pH was collected by filtration. This precipitate wasdissolved in MeOH, acidified with 2M HCl(aq) and concentrated. Theresidue was dissolved in EtOAc (100 mL) and diluted with water (50 mL).The pH of the aqueous layer was adjusted to 2 using 2 M HCl (aq). Thelayers were separated and the organic layer was dried (Na₂SO₄), filteredand concentrated giving the title compound as a white solid (73 mg,50%).

Example 1603-chloro-4-[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]-N,N-diethylbenzamide

The procedure to prepare3-[(5-chloro-4-hydroxypyridin-3-yl)sulfamoyl]-N,N-diethyl-benzamide wasused except that3-chloro-4-[(6-chloro-4-hydroxypyridazin-3-yl)-sulfamoyl]benzoic acidwas substituted for3-[(5-chloro-4-hydroxypyridin-3-yl)-sulfamoyl]benzoic acid and thereaction was heated at 60° C. for 2 hrs in a sealed tube (54%).

Example 1613-chloro-5-{[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]methyl}-N,N-diethylbenzamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that3-chloro-5-{[(6-chloro-4-methoxy-pyridazin-3-yl)sulfamoyl]methyl}-N,N-diethylbenzamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(8%).

Example 162N-(6-chloro-4-hydroxypyridazin-3-yl)-3-cyano-5-fluorobenzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except thatN-(6-chloro-4-methoxypyridazin-3-yl)-3-cyano-5-fluorobenzene-1-sulfonamidewas substituted forN-(6-chloro-4-methoxy-pyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(4%).

Example 1633-chloro-5-fluoro-N-[4-hydroxy-6-(trifluoromethyl)pyridazin-3-yl]benzene-1-sulfonamide

4-methoxy-6-(trifluoromethyl)pyridazin-3-amine (115 mg, 0.595 mmol) wasdissolved in THF (3 ml) under N₂ and sodium hydride added (60%, 26 mg,0.655 mmol) and the mixture stirred for 20 mins until gas evolutionceased. 3-chloro-5-fluorobenzene-1-sulfonyl chloride (136 mg, 0.595mmol) was added and the mixture stirred at room temperature overnight.The mixture was quenched with 2M HCl (5 mL), water was added (10 mL) andthe products extracted into DCM. The combined organic phases were dried(Na₂SO₄), the mixture filtered and the filtrate concentrated to dryness.Silica chromatography (eluent: 0-100% ethyl acetate in heptane) gave theintermediate methyl ether which was demethylated with BBr₃ in DCM as inprevious procedures. Aqueous work up and then purification by automatedreverse phase HPLC (low pH method) gave the title compound (17 mg, 8%).

Example 1641-(3,4-dichlorophenyl)-N-[5-hydroxy-2-(trifluoromethyl)pyrimidin-4-yl]methane-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that1-(3,4-dichlorophenyl)-N-[5-methoxy-2-(trifluoromethyl)pyrimidin-4-yl]methanesulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(37%).

Example 165N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2,5-dichlorothiophen-3-yl)methane-sulfonamide

To a stirring solution ofN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2,5-dichlorothiophen-3-yl)methanesulfonamide(170 mg, 0.39 mmol) in DCM (40 mL) at 0° C. was added 1M BBr₃ in DCM(1.18 mL, 1.18 mmol) and the reaction mixture was left to stir for 30mins. A further 500 μL of 1M BBr₃ in DCM was added and the mixture waskept at 0° C. for a further 90 mins. The reaction mixture was thenallowed to warm slightly (still kept below 10° C.) and a further 200 μLof 1M BBr₃ in DCM was added and the mixture was left to stir for afurther 45 mins. Then it was re-cooled back to 0° C. and quenched withice-cold water. The aqueous was then extracted with DCM (3×30 mL), thecombined organics were dried over MgSO₄ then concentrated under reducedpressure to yield a brown solid which was purified by automated reversephase HPLC (low pH method) to afford the title compound as a white solid(40 mg, 27%).

Example 1663,5-dichloro-N-(4-hydroxy-6-methanesulfonylpyridazin-3-yl)benzene-1-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyano-phenyl)methanesulfonamidewas used except that3,5-dichloro-N-(6-methane-sulfonyl-4-methoxypyridazin-3-yl)benzene-1-sulfonamidewas substituted forN-(6-chloro-4-methoxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methanesulfonamide(37%).

Example 1671-(3,5-dichlorophenyl)-N-(3-hydroxypyridin-4-yl)methanesulfonamide

To a solution of 4-amino-3-methoxypyridine (93 mg, 0.75 mmol) inpyridine (1 mL) was added (3,5-dichlorophenyl)methanesulfonyl chloride(195 mg, 0.75 mmol). The mixture was stirred at room temperature for 16h. The intermediate product was collected by filtration, dried invacuum, suspended in DCM (2 mL), then treated with 1M BBr₃ in DCM (0.52mL, 0.52 mmol) at 0° C. and the solution stirred at room temperature for16 h.

The reaction was quenched with water and ice and the resulting solidprecipitate was collected by filtration. The solid was warmed in EtOH (2mL) and 1M HCl (1 mL) for 4 hour at 70° C. The mixture was diluted withwater and the resulting solid precipitate was collected by filtrationand dried to afford1-(3,5-dichlorophenyl)-N-(3-hydroxypyridin-4-yl)methanesulfonamide as anoff-white solid (10 mg, 4%).

Example 1686-(2,5-dichlorothiophene-3-sulfonamido)-5-hydroxypyridine-3-carboxylicacid

To a solution of Methyl 6-(2,5-dichlorothiophene-3-sulfonamido)-5-hydroxypyridine-3-carboxylate (26mg, 0.07 mmol) in methanol (1.1 mL) was added 1M NaOH (1.5 mL) and themixture stirred at 60° C. for 5 hours. The mixture was filtered and thefiltrate acidified with 5 M HCl until pH below 3. The resulting solidwas filtered off, washed with water and dried to give6-(2,5-dichlorothiophene-3-sulfonamido)-5-hydroxy-pyridine-3-carboxylicacid as an off-white solid (10 mg, 40%).

Example 169N-(2-chloro-3-hydroxypyridin-4-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To a solution of 4-amino-2-chloro-3-methoxypyridine (160 mg, 1.0 mmol)in pyridine (1.5 mL) was added (3,5-dichlorophenyl)methanesulfonylchloride (260 mg, 1.0 mmol). The mixture was stirred at room temperaturefor 16 h. The solvent was evaporated and ethanol (5 mL) was added to theresidue followed by addition of water (2 mL). The intermediate productwas collected by filtration, dried in vacuum, suspended in CHCl₃ (6 mL),then treated with 1M BBr₃ in DCM (2.1 mL, 2.1 mmol) at 0° C. and thesolution stirred at room temperature for 16 h. The mixture is cooled inan ice bath and 1,2-propane-diol (0.7 mL) was added followed by theaddition of n-propanol (3 mL). The mixture was concentrated to removeCHCl₃, then diluted with n-propanol (3 mL) and 5 M HCl (0.4 mL) andheated to 80° C. After ½ hour the solution was cooled to roomtemperature and water added until first sign of precipitate. Afterstirring ½ hour, remaining product/boron complex was filtered off andadditional water was added to the residual solution. The obtained secondprecipitate was filtered off to afford1-(3,5-dichlorophenyl)-N-(2-chloro-3-hydroxypyridin-4-yl)methanesulfonamideas an off-white solid (175 mg, 48%).

Example 1703,5-dichloro-N-(2-chloro-3-hydroxypyridin-4-yl)benzene-1-sulfonamide

The procedure for preparation of1-(3,5-dichlorophenyl)-N-(2-chloro-3-hydroxypyridin-4-yl)methanesulfonamidewas used except that 3,5-dichlorobenzenesulphonyl chloride wassubstituted for (3,5-dichlorophenyl)methanesulfonyl chloride.

Example 171N-(3-hydroxypyridin-2-yl)-3-(trifluoromethyl)benzene-1-sulfonamide

3-(Trifluoromethyl)benzenesulfonyl chloride (773 mg) and2-amino-3-benzyloxypyridine (407 mg) were allowed to react according toprocedure A and then hydrogenated in water/sodium hydroxide usingpalladium on charcoal as catalyst. The catalyst was filtered off and theproduct was precipitated upon addition of hydrochloric acid (1 M). Theprecipitate was isolated by filtration, dried, and gave the titlecompound (153 mg, 24% yield).

Example 172N-(5-chloro-2-hydroxypyridin-3-yl)-1-(3,4-dichlorophenyl)methanesulfonamide

Prepared from (3,4-dichlorophenyl)methanesulfonyl chloride and3-amino-5-chloro-2-methoxypyridine (1.0 mmol) using procedures A and Bin 12% overall yield.

Example 173N-(5,6-dichloro-2-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

Prepared from (3,5-dichlorophenyl)methanesulfonyl chloride and3-amino-5,6-dichloro-2-methoxypyridine (1.23 mmol) using procedures Aand B in 80% overall yield.

Example 174N-(6-chloro-2-hydroxypyridin-3-yl)-1-(3,4-dichlorophenyl)methanesulfonamide

Prepared from (3,4-dichlorophenyl)methanesulfonyl chloride and3-amino-6-chloro-2-methoxypyridine (1.0 mmol) using procedures A and Bin 43% overall yield.

Example 175N-(6-chloro-2-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

Prepared from (3,5-dichlorophenyl)methanesulfonyl chloride and3-amino-6-chloro-2-methoxypyridine (1.0 mmol) using procedures A and Bin 88% overall yield.

Example 1765-bromo-N-(6-chloro-2-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide

Prepared from 5-bromo-6-chloropyridine-3-sulfonyl chloride and3-amino-6-chloro-2-methoxypyridine (1.0 mmol) using procedures A and B,omitting heating in ethanol and NaOH during procedure A, and reactingthe resulting compound after procedure B in 1 M NaOMe/MeOH at 80° C. for3 h followed by precipitation with acetic acid in water which gave thetitle compound in 33% overall yield.

Example 177N-(5,6-dibromo-3-hydroxypyrazin-2-yl)-1-(3,4-dichlorophenyl)methanesulfonamide

Isolated in low yield (5%) as a byproduct during the preparation ofABR-239417 (Example 75). A possible explanation for its formation wouldbe small amounts of bromine formed during the storage of 1 M borontribromide solutions. The bromine has then reacted with ABR-239417 togive the title compound.

Example 178N-(6-chloro-2-hydroxypyridin-3-yl)-1-[4-(trifluoromethyl)phenyl]methane-sulfonamide

Prepared from (4-trifluoromethylphenyl)methanesulfonyl chloride and3-amino-6-chloro-2-methoxypyridine (1.0 mmol) using procedures A and Bin 50% overall yield.

Example 179N-(6-chloro-2-hydroxypyridin-3-yl)-4-propylbenzene-1-sulfonamide

Prepared from 4-n-butylbenzenesulfonyl chloride and3-amino-6-chloro-2-methoxypyridine (1.0 mmol) using procedures A and Bin 57% overall yield.

Example 1803,4-dichloro-N-(6-chloro-2-hydroxypyridin-3-yl)benzene-1-sulfonamide

Prepared from 3,4-dichlorobenzenesulfonyl chloride and3-amino-6-chloro-2-methoxypyridine (1.0 mmol) using procedures A and Bin 32% overall yield.

Example 181N-(6-chloro-2-hydroxypyridin-3-yl)-1-(5,6-dichloropyridin-3-yl)methane-sulfonamide

Prepared from 1-(5,6-dichloropyridin-3-yl)methanesulfonylchloride and3-amino-6-chloro-2-methoxypyridine (3.0 mmol) using procedures A and B,omitting heating in ethanol and NaOH during procedure A, in 27% overallyield.

Example 182N-(6-chloro-2-hydroxypyridin-3-yl)-1-(5-chloro-6-methoxypyridin-3-yl)methane-sulfonamide

Prepared from ABR-239718 (0.3 mmol) by heating in 1 M NaOMe/MeOH at 80°C. for 72 h and isolating the precipitated sodium salt. The salt wasthen stirred in a mixture of acetic acid in methanol/water and the titlecompound (55 mg, 50% yield) was isolated by filtration.

Example 183N-(5-chloro-4-hydroxypyridin-3-yl)-1-(5,6-dichloropyridin-3-yl)methane-sulfonamide

Prepared from 1-(5,6-dichloropyridin-3-yl)methanesulfonylchloride (1.5mmol) and 3-amino-5-chloropyridin-4-ol (1.0 mmol) by heating in pyridineat 90° C. for 3 and partitioning the mixture between ethyl acetate,water and acetic acid. The organic phase was concentrated and theresidue was crystallised from methanol and gave the title compound (90mg, 24% yield).

Example 184N-(5-chloro-4-hydroxypyridin-3-yl)-1-(5-chloro-6-methoxypyridin-3-yl)methane-sulfonamide

Prepared from ABR-239726 (80 mg) by heating in 1 M NaOMe/MeOH at 80° C.for 18 h, then adding acetic acid and water and collecting theprecipitate. Drying the precipitate gave the title compound (67 mg, 83%yield).

Example 185N-(6-chloro-2-hydroxypyridin-3-yl)-1-[5-chloro-6-(pyrrolidin-1-yl)pyridin-3-yl]-methanesulfonamide

Prepared from ABR-239718 (60 mg) by heating in pyrrolidine (2 mL) at 80°C. for 3 h, concentrating the mixture and dissolving the residue in abs.ethanol and precipitating the title compound by adding acetic acid andwater. Yield after filtration and drying was 42 mg (64% yield).

Example 186N-(6-chloro-2-hydroxypyridin-3-yl)-1-[3-chloro-5-(ethylsulfanyl)phenyl]methane-sulfonamide

(3,5-dichlorophenyl)methanesulfonyl chloride and3-amino-6-chloro-2-methoxypyridine was reacted using procedure A. Theformed intermediate1-(3,5-dichlorophenyl)-N-(6-chloro-2-methoxy-pyridin-3-yl)methanesulfonamide(100 mg, 0.26 mmol) and sodium ethanethiolate (110 mg, 1.04 mmol) wereheated in DMF (1.5 mL) at 100 degree C. for 18 h. The mixture was thendiluted with water and acetic acid and the precipitate was isolated anddried to give the title compound (60 mg, 56% yield). H-nmr, 500 mHz, δ1.27 (t, 3H), 3.00 (q, 2H), 4.61 (s, 2H), 6.79 (broad signal, 1H), 7.28(d, 2H), 7.34 (s, 1H), 7.48 (d, 1H), 9.30 (bs, 1H), 12.50 (bs, 1H).(M+H)=393, (M−H)=391.

Example 1873,5-dichloro-N-[6-(ethanesulfonyl)-2-hydroxypyridin-3-yl]benzene-1-sulfonamide

Prepared from 3,5-dichlorobenzenesulfonylchloride and3-amino-6-ethanesulfonyl-2-methoxypyridine (1.0 mmol) using procedures Aand B in 74% overall yield.

Example 1881-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-2-hydroxypyridin-3-yl]methane-sulfonamide

Prepared from (3,5-dichlorophenyl)methanesulfonylchloride and3-amino-6-ethane-sulfonyl-2-methoxypyridine (1.0 mmol) using proceduresA and B in 81% overall yield.

Example 189N-(5-cyano-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide

To a solution ofN-(5-cyano-3-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)-methanesulfonamide(180 mg, 0.48 mmol) in DCM (25 mL) was added 1M BBr₃ in DCM (1.90 mL,1.90 mmol) in four portions over 5 hrs. The mixture was quenched by theaddition of saturated NaHCO₃ (20 mL) and more DCM was added (50 mL). Thephases were separated and the organic phase was washed with brine (20mL), dried (Na₂SO₄), the mixture filtered and the filtrate evaporated todryness to afford a brown oil which was purified by automated reversephase HPLC (low pH method) to afford the title compound as an off-whitesolid (32 mg, 18%).

Example 1905-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)-6-methylpyridine-3-sulfonamide

To a solution of 3-amino-4-hydroxy-5-chloropyridine (200 mg, 1.38 mmol)in pyridine (3 mL) at 80° C. was added a solution of the5-chloro-6-methylpyridine-3-sulfonyl chloride (219 mg, 0.97 mmol) in DCM(3 mL) dropwise. The mixture was stirred for 1 hr at this temperatureand then the pyridine was evaporated. The residue was purified byautomated reverse phase HPLC (low pH method). Further purification wasachieved by slurrying with 1:1 MeOH/water followed by filtration toafford the title compound as a purple solid (28 mg, 6%).

Example 191N-(5-chloro-4-hydroxypyridin-3-yl)-5-cyano-6-methoxypyridine-3-sulfonamide

A solution of5-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide(90 mg, 0.23 mmol) in NMP (1 mL) was treated with solid copper(I)cyanide (102 mg, 1.14 mmol) and the mixture stirred at 165° C. for 3hrs. The cooled reaction mixture was then partitioned between EtOAc (50mL) and 2M NH₃. The phases were separated and the organic phase waswashed with brine (5 mL), dried (Na₂SO₄), the mixture filtered and thefiltrate evaporated to dryness to afford a brown oil which was purifiedby automated reverse phase HPLC (low pH method) to afford the titlecompound as an off-white solid (9 mg, 11%).

Example 192N-(5-chloro-4-hydroxypyridin-3-yl)-6-methoxy-5-phenylpyridine-3-sulfonamide

A flask charged with5-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide(150 mg, 0.38 mmol), phenylboronic acid (56 mg, 0.46 mmol), cesiumcarbonate (495 mg, 1.52 mmol), Pd(dppf)Cl₂.DCM (31 mg, 0.04 mmol), EtOH(5 mL) and water (1 mL) was degassed with N₂ and then refluxed for 2hrs. The EtOH was evaporated and then water (5 mL) and EtOAc (60 ml)were added. The phases were separated and the organic phase was washedwith brine (20 mL), dried (Na₂SO₄), the mixture was filtered and thefiltrate evaporated to dryness to afford a black solid which waspurified by automated reverse phase HPLC (low pH method). Furtherpurification was achieved by slurrying in MeOH followed by filtration toafford the title compound as an off-white solid (22 mg, 13%).

Example 193N-(5-chloro-3-hydroxypyridin-2-yl)-5-phenylpyridine-3-sulfonamide

To a stirred solution ofN-(5-chloro-3-methoxypyridin-2-yl)-5-phenylpyridine-3-sulfonamide (150mg, 0.40 mmol) in DCM (6 mL) at −10° C. was added BBr₃ (300 mg, 1.20mmol). The reaction was allowed to warm to room temperature and wasstirred for 16 hrs. The reaction mixture was neutralised with saturatedNaHCO₃ and extracted with EtOAc. The organic layer was dried (Na₂SO₄),the mixture was filtered and the filtrate evaporated to dryness to givethe crude product which was purified by preparative TLC (eluent 10% MeOHin DCM). Further purification, by automated reverse phase HPLC (low pHmethod), gave the title compound as an off-white solid (40 mg, 28%).

Example 194N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3-chloro-5-cyanophenyl)methane-sulfonamide

The procedure to prepareN-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)-methanesulfonamidewas used except that (3-chloro-5-cyanophenyl)methanesulfonyl chloridewas substituted for (3,4-difluorophenyl)methanesulfonyl chloride and6-chloro-4-methoxypyridazin-3-amine was substituted for6-chloro-4-methoxypyridazin-3-amine (3%).

Example 1955-bromo-6-chloro-N-(6-chloro-4-hydroxypyridazin-3-yl)pyridine-3-sulfonamide

To a solution of5-bromo-6-chloro-N-(6-chloro-4-methoxypyridazin-3-yl)pyridine-3-sulfonamide(1.03 g, 2.49 mmol) in DCM (150 mL) was added 1M BBr₃ in DCM (15 mL, 15mmol) and the reaction stirred for 4 hrs. Neat BBr₃ (1 mL) was added andthe mixture warmed to 45° C. and stirred overnight. The cooled mixturewas diluted with more DCM (100 mL) and water, and then filtered. Thesolid was washed with water and dried in air to afford the titlecompound as a white solid.

Example 196N-(5-bromo-4-hydroxypyridin-3-yl)-3,5-dichlorobenzene-1-sulfonamide

To a stirred suspension of 3-amino-5-bromopyridin-4-ol (500 mg, 2.65mmol) in pyridine (15 mL) was added 3,5-dichlorobenzene-1-sulfonylchloride (585 mg, 2.38 mmol) in one portion. The reaction was stirredfor 1 hr at room temperature, concentrated and the residue diluted withEtOAc (100 ml) and washed with water (30 ml) and brine (30 ml). Theorganic phase was dried (Na₂SO₄), filtered and concentrated. The crudeproduct was triturated in the minimum volume of MeOH giving the desiredproduct as a pink solid (733 mg, 77% yield).

NMR and mass spectral data for Examples of the invention are shown inTable 1.

TABLE 1 ABR Chemical M ± H⁺ ref. Ex. name (m/z) ¹H NMR 238823   15-bromo-6-chloro-N-(5- (400 MHz, DMSO) δ 7.35 (dd,chloro-2-hydroxypyridin-3- 2H) 8.54 (d, 1H), 8.73 (d, 1H),yl)pyridine-3-sulfonamide 11.48 (s, 1H), 11.74 (d, 1H). 238066   2N-(4-hydroxypyridin-3-yl)- 250.9 (500 MHz, MeOD) δ 6.31 (d,benzenesulfonamide 1H), 7.44-7.52 (m, 1H), 7.54- 7.63 (m, 1H), 7.80-7.86(m, 2 H), 8.01 (d, 1H). 238845   3 N-(4-hydroxypyridin-3-yl)-4- 318.8(500 MHz, DMSO-d6) δ 6.09 (trifluoromethyl)-benzene-1- (d,1 H), 7.58(d,1H), 7.80 (s, sulfonamide 1H), 7.91 (d, 1H), 7.99 (d, 2H). 238846   4N-(4-hydroxypyridin-3-yl)-4- 334.8 (500 MHz, DMSO-d6) δ ppm(trifluoromethoxy)benzene-1- 6.10 (d, 1H), 7.51 (d, 2H), 7.58sulfonamide (d, 1H), 7.79 (s, 1H), 7.92 (d, 2H). 239202   5N-(5-chloro-3-hydroxy- 298.9 (500 MHz, MeOD) δ 4.59 (s,pyridin-2-yl)-1-phenyl- 2H), 7.17 (d, 1H), 7.35 (m, methanesulfonamide5H), 7.84 (s, 1H) 239224   6 N-(5-chloro-3-hydroxy- 355.1 (250 MHz,MeOD) δ 2.07 (t, pyridin-2-yl)-6-(pyrrolidin-1- 4H), 3.53 (bs, 4H), 6.68(d, yl)-pyridine-3-sulfonamide, 1H), 7.07 (d, 1H), 7.65 (d, formate salt1H), 8.03-8.12 (m, 2H), 8.58 (d, 1H). 239225   7 N-(5-chloro-3-hydroxy-286.0 (500 MHz, MeOD) δ 7.10 (d pyridin-2-yl)pyridine-3- 1H), 7.58-7.61(m, 1H), 7.63 sulfonamide (d, 1H), 8.45 (dt, 1H), 8.74 (dd, 1H), 9.17(d, 1H). 239226   8 6-chloro-N-(5-chloro-3- 320.0 (500 MHz, MeOD) δ 7.11(d hydroxypyridin-2-yl)- 1H), 7.57-7.68 (m, 2H), 8.36-pyridine-3-sulfonamide 8.45 (m, 2H), 8.97 (d, 1H). 239247   9N-(5-chloro-3-hydroxy- 366.6 (500 MHz, CDCl₃) δ 4.28 (s,pyridin-2-yl)-1-(3,5-dichloro- 2H), 7.07 (m, 2H),. 7.20-7.22phenyl)methanesulfonamide (m, 2H), 7.22-7.24 (m, 1H). 239248  10N-(5-chloro-3-hydroxy- 343.0 (500 MHz, MeOD) δ 1.22 (d,  pyridin-2-yl)-6-[(propan-2- 6H), 3.99-4.16 (m, 1H), 6.46  yl)amino]pyridine-3- (d, 1H), 7.06 (d, 1H), 7.65 (d,   sulfonamide 1H),7.85 (dd, 1H), 8.55 (d,   1H). 239249  11 5-bromo-6-chloro-N-[3- 405.5(500 MHz, MeOD) δ 1.23 (d,   hydroxy-5-(propan-2-yl)- 6H), 2.82 (h, 1H),7.17 (s, 1H),   pyridin-2-yl]pyridine-3- 7.33 (s, 1H), 8.63 (d, 1H),8.86   sulfonamide (d, 1H). 239254  12 N-(5-chloro-3-hydroxy- 324.0 (500MHz, MeOD) δ 4.93 (s,   pyridin-2-yl)-1-(3-cyano- 2H), 7.19 (d, 1H),7.54 (m,   phenyl)methanesulfonamide 1H), 7.69 (d, 1H), 7.72 (d,   1H),7.75 (s, 1H), 7.85 (s, 1H). 239269  13 (+/−)-5-bromo-6-chloro-N-[3-421.6 (500 MHz, MeOD) δ 1.22 (d,   hydroxy-5-(1-hydroxy- 3H), 2.78 (h,1H), 3.53-3.68   propan-2-yl)pyridin-2-yl]- (m, 2H), 7.13 (d, 1H), 7.36(s,   pyridine-3-sulfonamide 1H), 8.63 (d, 1H), 8.86 (d,   1H). 239270 14 5-bromo-6-chloro-N-(3- 363.9 (500 MHz, MeOD) δ 6.83 (dd,  hydroxypyridin-2-yl)- 1H), 7.19 (dd, 1H), 7.47 (d,  pyridine-3-sulfonamide 1H), 8.66 (d, 1H), 8.88 (d,   1H). 239271  15N-(5-chloro-3-hydroxy- 366.8 (500 MHz, MeOD) δ 5.05 (s,  pyridin-2-yl)-1-(2,4-dichloro- 2H), 7.18 (d,1H), 7.35 (dd  phenyl)methanesulfonamide 1H), 7.48-7.56 (m, 2H), 7.82   (s, 1H). 239272 16 N-(5-chloro-3-hydroxy- 323.8 (500 MHz, MeOD) δ 4.96 (s,  pyridin-2-yl)-1-(4-cyano- 2H), 7.17 (d, 1H), 7.57 (d,  phenyl)methanesulfonamide 2H), 7.72 (d, 2H), 7.80-7.88   (m, 1H). 239290 17 N-(5-chloro-3-hydroxy- 300.0 (500 MHz, MeOD) δ 4.92 (s,  pyridin-2-yl)-1-pyridin-3- 2H), 7.14 (d, 1H), 7.44 (dd,  ylmethanesulfonamide 1H), 7.81 (s, 1H), 7.89 (d, 1H),   8.51 (m, 2H).239291  18 5-bromo-N-(5-chloro-3- 432.8 (500 MHz, MeOD) δ 1.89-  hydroxypyridin-2-yl)-6- 2.04 (m, 4H), 3.72-3.89 (m,  (pyrrolidin-1-yl)pyridine-3- 4H), 7.09 (d, 1H), 7.67 (d,   sulfonamide1H), 8.26 (d, 1H), 8.57 (d,   1H). 239314  19 N-(5-chloro-3-hydroxy-334.8 (500 MHz, CDCl₃) δ 4.95 (s,   pyridin-2-yl)-1-(3,5-difluoro- 2H),6.90-7.12 (m, 3H), 7.20   phenyl)methanesulfonamide (s, 1H), 7.86 (s,1H). 239315  20 N-(5-chloro-3-hydroxy- (500 MHz, MeOD) δ 4.84 (s,  pyridin-2-yl)-1-(2,5-dichloro- 2H), 7.00 (s, 1H), 7.17 (d, 1H),  thiophen-3-yl)methane- 7.81 (s, 1H).   sulfonamide 239316  21N-(5-chloro-3-hydroxy- 366.8 (500 MHz, MeOD) δ 7.18 (d,  pyridin-2-yl)-1-(3,4-dichloro- 1H), 7.30 (dd, 1H), 7.50 (d,  phenyl)methanesulfonamide 1H), 7.54 (d, 1H), 7.86 (s, 1H). 239317  22N-(5-chloro-3-hydroxy- 350.8 (500 MHz, MeOD) δ 4.86 (s,  pyridin-2-yl)-1-(3-chloro-5- 2H), 7.12 (1H), 7.17-7.35  fluorophenyl)methanesulfon- (m, 3H), 7.85 (d, 1H).   amide 239318  231-(2,4-dichlorophenyl)-N-(4- 332.7 (500 MHz, CDCl₃) δ 4.64 (s,  hydroxypyridin-3-yl)- 2H), 6.47 (d,1H), 7.30 (dd,   methanesulfonamide1H), 7.45 (d, 1H), 7.54 (d,   1H), 7.67 (dd, 1H), 7.83 (d,   1H). 239321 24 1-(3,5-dichlorophenyl)-N-(4- 332.7 (500 MHz, MeOD) δ 4.52 (s,  hydroxypyridin-3-yl)- 2H), 6.48 (d,1H), 7.37 (m,   methanesulfonamide1H), 7.40 (d, 2H), 7.65 (dd,   1H), 7.83 (d, 1H). 239331  253,5-dichloro-N-(5-chloro-3- 352.8 (500 MHz, MeOD) δ 7.13 (d,  hydroxypyridin-2-yl)- 1H), 7.65-7.67 (m, 1H), 7.69-  benzene-1-sulfonamide 7.73 (m, 1H), 7.95-8.01 (m,   2H). 239332  263,4-dichloro-N-(5-chloro-3- 352.8 (500 MHz, MeOD) δ 7.12 (d,  hydroxypyridin-2-yl)- 1H), 7.66 (d, 1H), 7.71 (d,  benzene-1-sulfonamide 1H), 7.94 (dd, 1H), 8.20 (d,   1H). 239333  27N-(5-chloro-3-hydroxy- 332.8 (500 MHz, MeOD) δ 7.18 (d,  pyridin-2-yl)-1-(3-chloro- 1H), 7.28-7.38 (m, 3H), 7.40  phenyl)methanesulfonamide (s, 1H), 7.85 (s, 1H). 239334  28N-(5-chloro-3-hydroxy- 332.8 (500 MHz, MeOD) δ 7.17 (d,  pyridin-2-yl)-1-(4-chloro- 1H), 7.35 (s, 4H), 7.84 (s, 1H).  phenyl)methanesulfonamide 239335  29 N-(5-chloro-3-hydroxy- 332.8 (500MHz, MeOD) δ 5.07 (s,   pyridin-2-yl)-1-(2-chloro- 2H), 7.18 (d, 1H),7.31 (m,   phenyl)methanesulfonamide 1H), 7.35 (m, 1H), 7.44 (dd,   1H),7.52 (dd, 1H), 7.82 (s,   1H). 239336  30 N-(5-chloro-3-hydroxy- 366.8(500 MHz, MeOD) δ 5.04 (s,   pyridin-2-yl)-1-(2,5-dichloro- 2H), 7.19(d, 1H), 7.37 (dd,   phenyl)methanesulfonamide 1H), 7.44 (d, 1H), 7.55(d,   1H), 7.81 (d,1H), 239337  31 N-(5-chloro-3-hydroxy- 334.9 (500MHz, MeOD) δ 7.18 (dd,   pyridin-2-yl)-1-(3,4-difluoro- 2H), 7.20-7.27(m, 1H), 7.31   phenyl)methanesulfonamide (ddd, 1H), 7.86 (s, 1H).239338  32 1-(3,5-dichlorophenyl)-N-(3- 410.8 (500 MHz, MeOD) δ 3.17 (s,  hydroxy-5-methanesulfonyl- 3H), 7.35 (d, 2H), 7.44 (m,  pyridin-2-yl)methane- 1H), 7.50 (d, 1H), 8.30 (s, 1H).   sulfonamide239514  33 N-(5-chloro-3-hydroxy- 357.5 (500 MHz, MeOD) δ 4.92 (s,  pyridin-2-yl)-1-(3-chloro-5- 2H), 7.20 (d, 1H), 7.70 (s, 1H),  cyanophenyl)methane- 7.72 (s, 1H), 7.81 (d, 1H), 7.85   sulfonamide (s,1H). 239520  34 3-chloro-5-{[(5-chloro-3- 276.0 (500 MHz, MeOD) δ 4.91(s,   hydroxypyridin-2-yl)- 2H), 7.16 (d, 1H), 7.58 (s, 1H),  sulfamoyl]methyl}benzamide 7.81 (s, 2H), 7.87 (d, 1H). 239359  351-(5-chloro-2-fluorophenyl)- 351.3 (400 MHz, DMSO) δ 4.89 (s,  N-(5-chloro-3-hydroxy- 2H), 7.20 (d, 1H), 7.28 (m,  pyridin-2-yl)methane- 1H), 7.43-7.50 (m, 2H), 7.87   sulfonamide (s,1H), 10.35 (s, 2H). 239372  36 N-(6-chloro-4-hydroxy- 367.7 (500 MHz,MeOD) δ 4.78 (s,   pyridazin-3-yl)-1-(3,5-di- 2H), 6.57 (s, 1H), 7.38(d,   chlorophenyl)methane- 2H), 7.47 (m, 1H).   sulfonamide 239373  37N-(5-chloro-3-hydroxy- 366.8 (500 MHz, MeOD) δ 5.13 (s,  pyridin-2-yl)-1-(2,3-dichloro- 2H), 7.18 (d, 1H), 7.30 (m,  phenyl)methanesulfonamide 1H), 7.47 (dd, 1H), 7.55 (dd,   1H), 7.81 (s,1H). 239374  38 N-(5-chloro-3-hydroxy- 366.8 (250 MHz, MeOD) δ 5.27 (s,  pyridin-2-yl)-1-(2,6-dichloro- 2H), 7.15 (d, 1H), 7.27-7.47  phenyl)methanesulfonamide (m, 3H), 7.77 (d, 1H). 239405  39aN-(5-chloro-3-hydroxy- 380.8 (500 MHz, Methanol-d4) δ  pyridin-2-yl)-1-(3,5-dichloro- 1.78 (d, 3H),), 5.16 (s, 1H),  phenyl)ethane-1- 7.16 (d 1H), 7.36-7.50 (m,   sulfonamide, enantiomer 13H), 7.80 (s, 1H). 239406  39b N-(5-chloro-3-hydroxy- 380.8 (500 MHz,MeOD) δ 1.78 (d,   pyridin-2-yl)-1-(3,5-dichloro- 3H), 5.17 (s, 1H),7.16 (d,   phenyl)ethane-1- 1H), 7.34-7.45 (m, 3H), 7.80   sulfonamide,enantiomer 2 (s, 1H). 239183  40 5-bromo-N-(5-chloro-3- 364.3 (400 MHz,DMSO) δ 7.16 (s,   hydroxypyridin-2-yl)- 1H), 7.68 (s, 1H), 8.49 (d,  pyridine-3-sulfonamide 1H), 8.95 (s, 1H), 9.03 (d,   1H), 10.78 (s, 1H).239239  41 N-(5-chloro-3-hydroxy- 354.1 (400 MHz, DMSO) δ 7.19 (d,  pyridin-2-yl)-6-(trifluoro- 1H), 7.70 (d, 1H), 8.17 (d,  methyl)pyridine-3-sulfon- 1H), 8.60 (dd, 1H), 9.26 (d,   amide 1H),10.91 (s, 2H). 239262  42 N-(5-chloro-3-hydroxy- 369.1 (400 MHz, CDCl₃)δ 7.16 (s,   pyridin-2-yl)-3-(trifluoro- 1H), 7.32 (s, 1H), 7.41 (d,  methoxy)benzene-1- 1H), 7.54 (m, 1H), 7.77 (s,   sulfonamide 1H), 7.85(d, 1H) 239049  43 N-(5-bromo-3-hydroxy- 329.1 (400 MHz, CDCl₃) δ 7.25(s,   pyridin-2-yl)benzene- 1H), 7.48 (t, 3H), 7.56 (t, 1H),  sulfonamide 7.86-7.93 (m, 2H) 239050  44 N-(5-bromo-3-hydroxy- 403.2(400 MHz, DMSO) 6 7.29 (t,   pyridin-2-yl)-2,5-dichloro- 1H), 7.35 (s,1H), 7.75 (s, 1H),   thiophene-3-sulfonamide 10.76 (s, 2H) 239275  45N-(5-bromo-3-hydroxy- 413.0 (400 MHz, DMSO) δ 7.24 (d,  pyridin-2-yl)-3-(trifluoro- 1H), 7.61-7.66 (m, 1H), 7.67  methoxy)benzene-1- (d, 1H), 7.71 (m, 1H), 7.93 (s,   sulfonamide 1H),7.95-8.00 (m, 1H), 10.61   (s, 2H) 239304  46 5-bromo-N-(5-bromo-3-441.9 (400 MHz, DMSO) δ 7.30 (d,   hydroxypyridin-2-yl)-6- 1H), 7.78 (s,1H), 8.64 (d,   chloropyridine-3-sulfonamide 1H), 8.90 (d, 1H), 10.85(s,   2H) 239327  47 N-(5-bromo-3-hydroxy- 398.1 (400 MHz, DMSO) δ 7.26(d,   pyridin-2-yl)-6-(trifluoro- 1H), 7.73 (s, 1H), 8.14 (d,  methyl)pyridine-3-sulfon- 1H), 8.58 (d, 1H), 9.24 (s,   amide 1H), 10.84(s, 2H). 239345  48 5-bromo-N-(5-bromo-3- 438.0 (400 MHz, DMSO) δ 3.99(d,   hydroxypyridin-2-yl)-6- 3H), 7.20 (d, 1H), 7.71 (d,  methoxypyridine-3-sulfon- 1H), 8.43 (d, 1H), δ 8.65 (d,   amide 1H).239238  49 N-(3-hydroxypyridin-2-yl)-6- 320.1 (400 MHz, DMSO) δ 6.86(bs,   (trifluoromethyl)pyridine-3- 1H), 7.19 (d, 1H), 7.52 (bs,  sulfonamide 1H), 8.16 (dd, 1H), 8.57 (d,   1H), 9.26 (s, 1H), 12.69 (s,  1H) 239215  50 methyl 6-(2,5-dichloro- 383.1 (400 MHz, CDCl₃) δ 3.92(s,   thiophene-3-sulfonamido)-5- 3H), 7.22 (s, 1H), 7.64 (d,  hydroxypyridine-3- 1H), 7.92 (s, 1H), 12.22 (s,   carboxylate 1H) 239216 51 methyl 6-benzenesulfon- 309.2 (400 MHz, CDCl₃) δ 3.90 (d,  amido-5-hydroxypyridine-3- 3H), 6.84 (s, 1H), 7.47-7.60   carboxylate(m, 4H), 7.89 (s, 1H), 7.93-   7.96 (m, 2H), 12.042-12.52   (m, 1H)238979  52 4-bromo-3-fluoro-N-(4- 347.2 (400 MHz, DMSO) 6 6.10 (d,  hydroxypyridin-3-yl)- 1H), 7.52 (d, 1H), 7.58 (d,  benzene-1-sulfonamide 1H), 7.78 (s, 1H), 7.80 (d,   1H), 7.87 (t, 1H),11.42 (s,   1H). 239323  53 N-(5-chloro-2-hydroxy- 369.3 (400 MHz, DMSO)6 7.32 (d,   pyridin-3-yl)-3-(trifluoro- J = 2.7 Hz, 1H), 7.39 (d, J =  methoxy)benzene-1-sulfon- 2.5 Hz, 1H), 7.77-7.66 (m,   amide 2H), 7.84(s, 1H), 7.92-7.87   (m, 1H), 10.16 (s, 1H), 12.21   (s, 1H) 239324  54N-(5-chloro-2-hydroxy- 354.1 (400 MHz, DMSO) δ 7.05 (m,  pyridin-3-yl)-6-(trifluoro- 2H), 8.03 (m, 1H), 8.38 (d,  methyl)pyridine-3-sulfon- 1H), 9.07 (s, 1H), 11.33 (s,   amide 1H)239326  55 5-bromo-N-(5-chloro-2- 394.2 (400 MHz, DMSO) δ 3.99 (s,  hydroxypyridin-3-yl)-6- 3H), 7.38 (2xs, 2H), 8.47 (d,  methoxypyridine-3-sulfon- 1H), 8.57 (d, 1H), 10.04 (bs,   amide 1H),12.23 (bs, 1H). 238857  56 2,5-dichloro-N-(5-chloro-3- (500 MHz, DMSO) δ7.29 (d,   hydroxypyridin-2-yl)- 1H), 7.37 (s, 1H), 7.72 (s, 1H),  thiophene-3-sulfonamide 10.8 (bs, 1H), 10.9 (bs, 1H). 238733  57N-(5-chloro-4- (500 MHz, MeOD) δ 7.93 (d,   hydroxypyridin-3-yl)-6- 1H),7.98 (d, 1H), 8.06 (d,   (trifluoromethyl)pyridine-3- 1H), 8.42 (dd,1H), 9.04 (d,   sulfonamide 1H). 238734  58 5-bromo-6-chloro-N-(5- (500MHz, DMSO) δ 7.90 (d,   chloro-4-hydroxypyridin-3- 1H), 8.10 (d, 1H),8.56 (d,   yl)pyridine-3-sulfonamide 1H), 8.69 (d, 1H), 10.2 (bs,   1H),12.1 (bs, 1H). 238901  59 5-bromo-N-(5-chloro-4- (500 MHz, DMSO) δ 3.99(s,   hydroxypyridin-3-yl)-6- 3H), 7.87 (d, 1H), 8.07 (d,  methoxypyridine-3- 1H), 8.39 (d, 1H), 8.46 (d,   sulfonamide 1H), 9.8(bs, 1H), 12.1 (bs,   1H). 239044  60 5-bromo-N-(5-chloro-4- (500 MHz,DMSO) δ 7.90 (d,   hydroxypyridin-3-yl)- 1H), 8.09 (d, 1H), 8.41 (t,1H),   pyridine-3-sulfonamide 8.84 (d, 1H), 8.96 (d, 1H),12.1   (bs,1H). 238580  61 5-bromo-6-chloro-N-(4- (500 MHz, DMSO) δ 6.16 (d,  hydroxypyridin-3-yl)- 1H), 7.62 (d, 1H), 7.86 (s,  pyridine-3-sulfonamide 1H), 8.56 (d, 1H), 8.68 (d,   1H). 238868  625-bromo-N-(4- (500 MHz, DMSO) δ 3.98 (s,   hydroxypyridin-3-yl)-6- 3H),6.12 (d, 1H), 7.60 (d,   methoxypyridine-3- 1H), 7.83 (d, 1H), 8.40 (d,  sulfonamide 1H), 8.45 (d, 1H), 11.5 (bs,   1H). 238581  632,5-dichloro-N-(4- (500 MHz, DMSO) δ 6.20 (d,   hydroxypyridin-3-yl)-1H), 7.41 (s, 1H), 7.64 (d,   thiophene-3-sulfonamide 1H), 7.79 (d, 1H),11.6 (bs,   1H). 238582  64 N-(4-hydroxypyridin-3-yl)-6- (500 MHz, DMSO)δ 6.34 (d,   (trifluoromethyl)pyridine-3- 1H), 7.68 (dd, 1H), 7.95 (d,  sulfonamide 1H), 8.08 (d, 1H), 8.44 (dd,   1H), 9.07 (bs, 1H). 238615 65 3,4-difluoro-N-(4-hydroxy- (500 MHz, DMSO) δ 6.13 (d,  pyridin-3-yl)benzene-1- 1H), 7.57-7.68 (m, 3H), 7.80   sulfonamide (d,1H), 7.89-7.96 (m, 1H). 239168  66 3,4-dichloro-N-(4-hydroxy- (500 MHz,DMSO) δ 6.13 (d,   pyridin-3-yl)benzene-1- 1H), 7.60 (d, 1H), 7.70 (dd,  sulfonamide 1H), 7.77-7.82 (m, 2H), 8.04   (d, 1H). 238612  67N-(2-hydroxypyridin-3-yl)-6- (500 MHz, DMSO) δ 6.17 (t,  (trifluoromethyl)pyridine-3- 1H), 7.18 (s, 1H), 7.42 (s, 1H),  sulfonamide 8.11 (d, 1H), 8.45 (d, 1H),   9.11 (s, 1H), 10.2 (bs, 1H),  11.8 (bs, 1H). 238610  68 5-bromo-6-chloro-N-(2- (500 MHz, DMSO) δ 6.21(t,   hydroxypyridin-3-yl)- 1H), 7.25 (bs, 1H), 7.48 (dd,  pyridine-3-sulfonamide 1H), 8.61 (d, 1H), 8.73 (d,   1H), 10.1 (bs, 1H),12.0 (bs,   1H). 238611  69 2,5-dichloro-N-(2-hydroxy- (500 MHz, DMSO) δ6.20 (t,   pyridin-3-yl)thiophene-3- 1H), 7.25 (dd, 1H), 7.37-7.42  sulfonamide (m, 2H), 9.8 (bs, 1H), 12.0 (bs,   1H). 239286  70N-(6-chloro-4-hydroxy- (500 MHz, DMSO) δ 4.55 (s,  pyridin-3-yl)-1-(3,4-dichloro- 2H), 6.87 (bs, 1H), 7.42(dd,  phenyl)methanesulfonamide 1H), 7.63 (d, 1H), 7.70 (d,   1H), 8.02 (bs,1H), 9.30 (bs,   1H), 11.90 (bs, 1H). 238942  71 5-bromo-N-(5-chloro-3-(500 MHz, MeOD) δ 4.07 (s,   hydroxypyridin-2-yl)-6- 3H), 7.11 (d, 1H),7.68 (d,   methoxypyridine-3- 1H), 8.50 (d, 1H), 8.74 (d,   sulfonamide1H). 239281  72 3,4-dichloro-N-(3- (500 MHz, DMSO) δ 7.23 (d,  hydroxypyridin-4- 1H), 7.75-7.85 (m, 4H), 8.01  yl)benzene-1-sulfonamide (s, 1H), 13.0 (bs, 1H). 239167  732,5-dichloro-N-(6-chloro-4- (500 MHz, DMSO) δ 6.80 (s,  hydroxypyridin-3- 1H), 7.25 (s, 1H), 8.00 (s, 1H),  yl)thiophene-3-sulfonamide 10.24 (bs, 1H), 11.80 (bs, 1H). 239129  742,5-dichloro-N-(5-chloro-2- (500 MHz, DMSO) δ 7.37 (d,  hydroxypyridin-3- 1H), 7.43 (s, 1H), 7.49 (d,  yl)thiophene-3-sulfonamide 1H), 10.25 (bs, 1H), 12.30 (bs,   1H). 239417 75 N-(5-bromo-3-hydroxy- (500 MHz, DMSO) δ 4.85 (s,  pyrazine-2-yl)-3,4-dichloro- 2H), 7.27 (d, 1H), 7.59 (s,  phenylmethanesulfonamide 1H), 7.65 (d, 1H), 7.70-7.90   (bs, 1H), 10.60(bs, 1H), 13.30   (bs, 1H). 239462  76 N-(5-bromo-3- 335.8 (500 MHz,MeOD) δ 4.77 (s,   hydroxypyrazin-2-yl)-1-(3,4- 2H), 6.55 (s, 1H), 7.19(s, 1H),   dichlorophenyl)methane- 7.23-7.31 (m, 1H), 7.32-  sulfonamide 7.39 (m, 1H). 239468  77 1-(3,5-dichlorophenyl)-N-[3- 439.2(500 MHz, MeOD), 6 1.30 (d,   hydroxy-5-(propane-2- 6H), 3.34 (m, 1H),7.33 (s,   sulfonyl)pyridin-2- 2H), 7.43 (s, 2H), 8.26 (s, 1H),  yl]methanesulfonamide 239604  78 N-(5-chloro-3-hydroxy- 367.8 (500 MHz,DMSO) δ 4.87 (s,   pyrazin-2-yl)-1-(3,5- 2H), 7.37 (s, 2H), 7.64 (s,1H),   dichlorophenyl)methane- 7.78 (s, 1H).   sulfonamide 239614  795-bromo-N-(5-chloro-4- 456.0 (500 MHz, MeOD) δ 7.13 (d,  hydroxypyridin-3-yl)-6- 2H), 7.26 (t, 1H), 7.42 (t, 2H),  phenoxypyridine-3- 7.98 (s, 1H), 8.01 (s, 1H), 8.29   sulfonamide (d,1H), 8.41 (d, 1H). 239618  80 N-(5-bromo-3-hydroxy- 411.8 (250 MHz,DMSO) δ 4.83 (s,   pyrazin-2-yl)-1-(3,5- 2H), 7.39 (d, 2H), 7.54 (m,  dichlorophenyl)methane- 1H), 7.63 (s, 1H).   sulfonamide 239494  81N-(6-chloro-4-hydroxy- 367.8 (500 MHz, MeOD) δ 4.96 (s,  pyridazin-3-yl)-1-(2,4- 2H), 6.51 (s, 1H), 7.37 (d, 1H),  dichlorophenyl)methane- 7.52-7.60 (m, 2H).   sulfonamide 239498  821-(3,5-dichlorophenyl)-N-(4- −458.1 (400 MHz, MeOD) δ 4.78 (s,  hydroxy-6-iodopyridazin-3- 2H), 6.72 (s, 1H), 7.35 (d, 2H),  yl)methanesulfonamide 7.61 (t, 1H). 239497  83 N-(6-bromo-4-hydroxy-412.1 (400 MHz, MeOD) δ 4.63 (s,   pyridazin-3-yl)-1-(3,5- 2H), 6.50 (s,1H), 7.24 (d, 2H),   dichlorophenyl)methane- 7.33 (t, 1H).   sulfonamide239570  84 3-bromo-N-(5-bromo-4- 436.8 (500 MHz, DMSO) δ 3.91 (s,  hydroxypyridin-3-yl)-4- 3H), 7.22 (d, 1H), 7.75 (dd,   methoxybenzene-1-1H), 7.82 (s, 1H), 7.99 (d, 1H),   sulfonamide 8.10 (s, 1H). 239571  85N-(6-chloro-4-hydroxy- 358.9 (500 MHz, DMSO) δ 4.96 (s,  pyridazin-3-yl)-1-(2-chloro- 2H), 6.48 (s, 1H), 7.73 (d, 1H),  5-cyanophenyl)methane- 7.87 (dd, 1H), 7.95 (d, 1H).   sulfonamide 239593 86 N-(5-chloro-4-hydroxy- 377.9 (500 MHz, DMSO) δ 7.17 (m,  pyridin-3-yl)-6-phenoxy- 3H), 7.27 (m, 1H), 7.45 (m,  pyridine-3-sulfonamide 2H), 7.85 (s, 1H), 8.03 (s, 1H),   8.19 (dd, 1H),8.45 (d, 1H). 239522  87 N-(6-chloro-4-hydroxy- 366.9 (500 MHz, MeOD) δ4.50 (s,   pyridin-3-yl)-1-(3,5- 365.9 2H), 6.78 (s, 1H), 7.40 (s, 3H),  dichlorophenyl)methane- 8.02 (s, 1H).   sulfonamide 239676  881-(3-chlorophenyl)-N-[5- 391.8 (500 MHz, MeOD) δ 1.26 (t,  (ethanesulfonyl)-3-hydroxy- 3H), 3.26-3.30 (m, 2H), 4.79  pyrazin-2-yl]methane- (s, 2H), 7.26-7.38 (m, 3H),   sulfonamide 7.42 (s,1H), 7.80 (s, 1H). 239610  89 3,5-dichloro-N-(5-chloro-4- 352.9 (500MHz, DMSO-d6) δ 7.69-   hydroxypyridin-3-yl)- 351.9 7.83 (m, 2H), 7.84(s, 1H),   benzene-1-sulfonamide 7.92 (s, 1H), 8.05 (s, 1H). 239486  90N-(6-chloro-4-hydroxy- 333.8 (500 MHz, MeOD) δ 4.99 (s,  pyridazin-3-yl)-1-(2-chloro- 2H), 6.54 (s, 1H), 7.31-7.41  phenyl)methane-sulfonamide (m, 2H), 7.45 (d, 1H), 7.56   (dd, 1H).239567  91 5-bromo-N-(5-bromo-4- 437.8 (500 MHz, MeOD) δ 4.04 (s,  hydroxypyridin-3-yl)-6- 3H), 8.05 (s, 1H), 8.08 (s, 1H),  methoxypyridine-3- 8.27 (d, 1H), 8.46 (d, 1H).   sulfonamide 239637  92N-(6-bromo-5-chloro-3- 444.7 (500 MHz, MeOD) δ 7.29 (s,  hydroxypyridin-2-yl)-1-(3,5- 1H), 7.37 (s, 2H), 7.46 (s, 1H).  dichlorophenyl)methane-   sulfonamide 239654  931-(2-chlorophenyl)-N-(4- 377.8 (500 MHz, MeOD) δ 3.28 (s,  hydroxy-6-methanesulfonyl- 3H), 5.00 (s, 2H), 6.98 (s, 1H),  pyridazin-3-yl)m ethane- 7.25-7.39 (m, 2H), 7.44 (d,   sulfonamide 1H),7.57 (d, 1H). 239532  94 N-(6-chloro-4-hydroxy- 351.8 (250 MHz, MeOD) δ4.78 (s,   pyridazin-3-yl)-1-(3-chloro- 2H), 6.54 (s, 1H), 7.13 (d, 1H),  5-fluorophenyl)methane- 7.18-7.31 (m, 2H).   sulfonamide 239477  953,5-dichloro-N-(6-chloro-4- 353.6 (500 MHz, MeOD) _ 6.48 (s,  hydroxypyridazin-3-yl)- 1H), 7.77 (s, 1H), 8.03 (s, 2H).  benzene-1-sulfonamide 239485  96 N-(6-chloro-4-hydroxy- 333.8 (500 MHz,MeOD) δ 4.78 (s,   pyridazin-3-yl)-1-(3-chloro- 2H), 6.54 (s, 1H),7.29-7.41   phenyl)methanesulfonamide (m, 3H), 7.43 (s, 1H). 239565  97N-(5-bromo-4-hydroxy- (500 MHz, DMSO) δ 4.61 (s,  pyridin-3-yl)-1-(3,5-dichloro- 2H), 7.52 (s, 2H), 7.57 (s, 1H),  phenyl)methanesulfonamide 7.69 (s, 1H), 8.18 (s, 1H),   11.99 (s, 1H).239605  98 3-[(5-chloro-4-hydroxy- 384.1 (500 MHz, DMSO) δ 0.96 (s,  pyridin-3-yl)sulfamoyl]-N,N- 3H), 1.15 (s, 3H), 3.07 (s, 4H),  diethylbenzamide 7.59 (m, 2H), 7.68 (s, 1H),   7.81-7.87 (m, 2H), 8.03(s,   1H), 11.96 (s, 1H). 239635  99 1-(3,4-difluorophenyl)-N-(4- 379.9(500 MHz, DMSO) δ 3.23 (s, hydroxy-6-methanesulfonyl- 3H), 4.78 (d, 2H),6.57 (s, 1H), pyridazin-3-yl)methane- 7.16 (s, 1H), 7.32-7.51 (m,sulfonamide 2H). 239591 100 3-chloro-N-(5-chloro-4- 332.9 (500 MHz,DMSO) δ 2.38 (s, hydroxypyridin-3-yl)-4- 3H), 7.51 (d, 1H), 7.63 (dd,methylbenzene-1- 1H), 7.83 (d, 1H), 7.85 (d, sulfonamide 1H), 8.04 (d,1H). 239612 101 5-bromo-N-(5-chloro-4- 422.0 (500 MHz, MeOD) δ 1.36 (d,hydroxypyridin-3-yl)-6- 6H), 5.38 (hept, 1H), 7.98 (s,(propan-2-yloxy)pyridine-3- 1H), 8.03 (s, 1H), 8.25 (d, 1H), sulfonamide8.40 (d, 1H). 239607 102 3-chloro-N-(5-chloro-4- 402.8 (500 MHz, DMSO) δ7.74 (s, hydroxypyridin-3-yl)-4- 1H), 7.85 (s, 2H), 8.06 (s, 1H),(trifluoromethoxy)benzene-1- 8.12 (s, 1H). sulfonamide 239613 103N-(5-cyano-3-hydroxy- 358.8 (250 MHz, DMSO, 368K) δpyrazin-2-yl)-1-(3,5- 4.77 (s, 2H), 7.42 (s, 2H), 7.53dichloro-phenyl)methane- (s, 1H), 7.70 (s, 1H). sulfonamide 239512 1041-(3,5-dichlorophenyl)-N-[4- −438.4 (400 MHz, MeOD) δ 1.04 (t,hydroxy-6-(propane-1- 3H), 1.74 (m, 2H), 3.33 (m, sulfonyl)pyridazin-3-2H), 4.71 (s, 2H), 6.88 (s, 1H), yl]methanesulfonamide 7.36 (s, 1H),7.43 (s, 2H). 239413 105 N-(5-chloro-3-hydroxy- −357.3 (400 MHz, MeOD) δ3.61 (s, pyridin-2-yl)-1-(3,5- 6H), 4.67 (s, 2H), 6.34 (s, 1H),dimethoxy-phenyl)methane- 6.38 (d, 2H), 7.05 (s, 1H), 7.50 sulfonamide(dd, 1H), 7.75 (s, 1H). 239428 106 5-chloro-N-(5-chloro-3- 363.1 (400MHz, DMSO) δ 3.11 (s, hydroxypyridin-2-yl)-6- 6H), 7.15 (d, 1H), 7.74(d, (dimethylamino)pyridine-3- 1H), 8.09 (d, 1H), 8.57 (d, sulfonamide1H), 10.22 (s, 1H), 10.88 (s, 1H). 239553 107 N-(2-chloro-4-hydroxy-367.8 (500 MHz, DMSO) δ 4.08 (s, pyrimidin-5-yl)-1-(3,5- 1H), 4.62 (s,2H), 7.47 (m, dichlorophenyl)methane- 2H), 7.60 (m, 1H), 7.78 (s,sulfonamide 1H), 9.45 (s, 1H). 239467 108 1-(3,5-dichlorophenyl)-N-[5-−423.3 (400 MHz, MeOD) δ 8.22 (s, (ethanesulfonyl)-3-hydroxy- 1H), 1.17(t, 3H), 3.14 (q, 2H), pyridin-2-yl]methane- 7.23 (s, 2H), 7.33 (s,1H),7.36 sulfonamide (s, 1H). 239478 109 3,4-dichloro-N-(6-chloro-4-353.7 (500 MHz, MeOD) δ 6.46 (s, hydroxypyridazin-3- 1H), 7.76 (d, 1H),7.97 (dd, yl)benzene-1-sulfonamide 1H), 8.23 (d, 1H). 239568 110N-(5-chloro-4-hydroxy- 367.0 (500 MHz, DMSO-d6) δ 4.61pyridin-3-yl)-1-(3,5-dichloro- (s, 3H), 7.52 (d, 2H), 7.57 (t,phenyl)methanesulfonamide 1H), 7.69 (d, 1H), 8.10 (d, 1H), 8.97 (s, 1H),12.02 (s, 1H). 239524 111 1-(3,5-dichlorophenyl)-N-[6- 426.2 (400 MHz,DMSO) δ 1.16 (t, (ethanesulfonyl)-4-hydroxy- 3H), 3.37 (q, 2H), 4.80 (s,2H), pyridazin-3-yl]methane- 6.59 (s, 1H), 7.11 (s, 3H), 7.37sulfonamide (d, 2H), 7.57 (m, 1H). 239619 1121-(3,5-dichlorophenyl)-N-(3- 412.0 (250 MHz, DMSO, 368K) δhydroxy-5-methanesulfonyl- 3.22 (s, 3H), 4.82 (s, 2H), 7.44pyrazin-2-yl)methane- (s, 2H), 7.54 (s, 1H), 7.85 (s, sulfonamide 1H).239491 113 2,5-dichloro-N-(6-chloro-4- 360.1 (400 MHz, DMSO) δ 7.33 (s,hydroxypyridazin-3- 1H), 6.50 (s, 1H). yl)thiophene-3-sulfonamide 239502114 5-bromo-N-(6-chloro-4- 395.3 (500 MHz, DMSO) δ 4.03 (s,hydroxypyridazin-3-yl)-6- 3H), 6.54 (s, 1H), 8.47 (d, 1H),methoxypyridine-3- 8.70 (d, 1H). sulfonamide 239461 115N-(6-chloro-4-hydroxy- 367.7 (500 MHz, MeOD) δ 5.05 (s,pyridazin-3-yl)-1-(2,3- 2H), 6.54 (s, 1H), 7.29-7.36dichlorophenyl)methane- (m, 1H), 7.52 (d, 1H), 7.57 (d, sulfonamide 1H).239501 116 N-(6-chloro-4-hydroxy- −368.3 (400 MHz, DMSO) δ 6.52 (d,pyridazin-3-yl)-3-(trifluoro- 1H), 7.73 (dd, Hz, 2H), 7.90methoxy)benzene-1- (s, 1H), 7.97 (d, 1H). sulfonamide 239600 1176-(azetidin-1-yl)-5-bromo-N- 418.9 (500 MHz, DMSO) δ 2.20-(5-chloro-4-hydroxypyridin- 2.34 (m, 2H), 4.31 (t, 4H),3-yl)pyridine-3-sulfonamide 7.84 (s, 1H), 8.00-8.15 (m, 2H), 8.31 (s,1H). 239525 118 1-(3,5-dichlorophenyl)-N-[4- 440.4 (400 MHz, MeOD) δ1.31 (d, hydroxy-6-(propane-2- 6H), 3.55-3.60 (m, 1H), 4.73sulfonyl)pyridazin-3- (s, 2H), 6.90 (s, 1H), 7.34 (s,yl]methanesulfonamide 1H), 7.47 (s, 2H). 239611 1195-bromo-N-(5-chloro-4- 407.9 (500 MHz, MeOD) δ 1.39 (t,hydroxypyridin-3-yl)-6- 3H), 4.46 (q, 2H), 7.95 (s, ethoxypyridine-3-1H),), 8.02 (s, 1H), 8.24 (d, sulfonamide 1H), 8.41 (d, 1H). 239411 1205-bromo-N-(5-chloro-3- 407.1 (400 MHz, CDCl₃) δ 3.16 (d,hydroxypyridin-2-yl)-6- 6H), 7.16 (s, 1H), 7.41 (s, 1H),(dimethylamino)pyridine-3- 8.12 (s, 1H), 8.55 (s, 1H). sulfonamide239628 121 N-(6-chloro-4-hydroxy- 310.8 (500 MHz, DMSO-d6) δ 6.53pyridazin-3-yl)-3-cyano- (m, 1H), 7.82 (m, 1H), 8.14 (d,benzene-1-sulfonamide 1H), 8.24 (d, 1H), 8.36 (s, 1H). 239554 1223-chloro-N-(5-chloro-4- 349.0 (500 MHz, DMSO-d6) δ 3.91hydroxypyridin-3-yl)-4- (s, 3H),), 7.25 (d, 1H), 7.70 methoxy-benzene-1-(dd, 1H), 7.79-7.84 (m, 1H), sulfonamide 7.86 (d, 1H), 8.03 (m, 1H).239555 123 3-bromo-N-(5-chloro-4- 392.9 (500 MHz, DMSO) δ 3.91 (s,hydroxypyridin-3-yl)-4- 3H), 7.21 (d, 1H), 7.75 (dd, methoxybenzene-1-1H), 7.82 (s, 1H), 8.00 (d, 1H), sulfonamide 8.04 (s, 1H). 239457 1241-(3,5-dichlorophenyl)-N-[3- 439.1 (400 MHz, DMSO) δ 0.90 (t,hydroxy-5-(propane-1- 3H), 1.55 (m, 2H), 3.22-3.27 sulfonyl)pyridin-2-(m, 2H), 4.88 (s, 2H), 7.29 (d, yl]methanesulfonamide 2H), 7.41 (d, 1H),7.54 (m, 1H), 8.17 (s,1H). 239449 125 N-(6-chloro-4-hydroxy- 367.7 (500MHz, MeOD) δ 4.78 (s, pyridazin-3-yl)-1-(3,4- 2H), 6.55 (s, 1H), 7.32(d, 1H), dichlorophenyl)methane- 7.53 (d, 1H), 7.57 (s, 1H). sulfonamide239450 126 1-(3,5-dichlorophenyl)-N-(4- 412.2 (400 MHz, MeOD) δ 3.20 (s,hydroxy-6- 3H), 4.72 (s, 2H), 6.92 (s, 1H), methanesulfonylpyridazin-3-7.35 (s, 1H), 7.48 (s, 2H), yl)methanesulfonamide 239465 127N-(5-chloro-3-hydroxy- 330.2 (400 MHz, MeOD) δ 4.91 (s,pyridin-2-yl)-1-(5-cyano- 2H), 7.16 (d, 1H),), 7.73 (d,thiophen-3-yl)methane- 1H), 7.76-7.84 (m, 2H). sulfonamide 239574 1285-bromo-6-chloro-N-[4- 431.9 (500 MHz, MeOD) δ , 6.91 (s,hydroxy-6-(trifluoromethyl)- 1H)., 8.33 (s, 2H), 8.54 (d, 1H)pyridin-3-yl]pyridine-3- sulfonamide 239592 129 5-bromo-N-(5-chloro-4-(500 MHz, DMSO) δ 1.61 (s, hydroxypyridin-3-yl)-6- 6H), 7.85 (s, 1H),8.04 (s, 1H), (piperidin-1-yl)pyridine-3- 8.19 (d, 1H), 8.43 (d, 1H).sulfonamide 239641 130 N-(5-chloro-6-cyano-3- 392.0 (500 MHz, MeOD) δ4.87 (s, hydroxypyridin-2-yl)-1-(3,5- 2H), 7.24 (s, 1H), 7.35 (d, 2H),dichlorophenyl)methane- 7.47 (t, 1H). sulfonamide 239466 131N-[5-(cyclopentanesulfonyl)- 465.3 (400 MHz, DMSO) δ 1.59 (m,3-hydroxypyridin-2-yl]-1- 4H), 1.84 (d, 4H), 3.79 (m,(3,5-dichlorophenyl)- 1H), 4.99 (s, 2H), 7.31 (s, 2H),methanesulfonamide 7.43 (s, 1H), 7.61 (s, 1H), 8.27 (s, 1H). 239589 132N-[4-hydroxy-6-(trifluoro- 333.9 (500 MHz, MeOD) δ 2.60 (s,methyl)pyridin-3-yl]-6- 3H), 7.05 (s, 1H), 7.44 (d, 1H),methylpyridine-3- 8.06 (dd, 1H), 8.50 (s, 1H), sulfonamide 8.78 (d, 1H).239576 133 1-(3,5-dichlorophenyl)-N-[4- 400.9 (500 MHz, MeOD) δ 4.55 (s,hydroxy-6-(trifluoromethyl)- 2H), 7.12 (s, 1H), 7.34 (m,1H),pyridin-3-yl]methane- 7.39 (d, 2H), 8.36 (s, 1H). sulfonamide 239671 134N-(5-chloro-3-hydroxy-6- 444.8 (500 MHz, MeOD) δ 3.31 (bs,methanesulfonylpyridin-2- 3H), 4.93 (s, 2H), 6.98 (s, 1H),yl)-1-(3,5-dichlorophenyl)- 7.38 (d, 2H), 7.40 (s, 1H). methanesulfonamide 239573 135 1-(3,4-dichlorophenyl)-N-[4- 400.8 (500 MHz,MeOD) δ 4.54 (s, hydroxy-6-(trifluoromethyl)- 2H), 7.08 (s, 1H), 7.34(dd, pyridin-3-yl]methane- 1H), 7.43 (d, 1H), 7.56 (d, sulfonamide 1H),8.32 (s, 1H). 239481 136 N-(5-chloro-3-hydroxy- 407.2 (400 MHz, DMSO) δ3.22 (s, pyridin-2-yl)-6-(dimethyl- 6H), 3.44 (s, 3H), 7.18 (d,amino)-5-methanesulfonyl- 1H),7.76 (d, 1H), 8.71 (d, 1H),pyridine-3-sulfonamide 8.79 (d, 1H). 239575 137 5-bromo-N-[4-hydroxy-6-427.9 (500 MHz, MeOD) δ 3.93 (s, (trifluoromethyl)pyridin-3- 3H), 6.95(s, 1H), 8.17 (d, 1H), yl]-6-methoxypyridine-3- 8.31 (s, 1H),8.38 (s,1H) sulfonamide 239566 138 N-(5-cyano-4-hydroxy- 358.0 (500 MHz,DMSO-d6) δ 4.64 pyridin-3-yl)-1-(3,5-dichloro- (s, 2H), 7.48 (d, 2H),7.57 (m, phenyl)methanesulfonamide 1H), 7.70 (d, 1H), 8.39 (d, 1H), 9.10(s, 1H). 239531 139 1-(3,5-dichlorophenyl)-N-[4- 456.3 (400 MHz, MeOD) δ1.85- hydroxy-6-(3-hydroxy- 1.951 (m, 2H), 3.40 (t, 2H),propanesulfonyl)pyridazin-3- 3.63 (t, 2H), 4.68 (s, 2H), 6.78yl]methanesulfonamide (s, 1H), 7.38 (d, 1H), 7.39 (s, 2H). 239499 140N-[6-(cyclopentanesulfonyl)- 466.2 400 MHz, MeOD) δ 1.70 (m,4-hydroxypyridazin-3-yl]-1- 4H), 2.00 (m, 4H), 3.91 (m,(3,5-dichlorophenyl)- 1H), 4.71 (s, 2H), 6.94 (s, 1H),methanesulfonamide 7.34 (s, 1H), 7.49 (s, 2H). 239717 141(+/−)-N-(5-bromo-3-hydroxy- 479.8 (500 MHz, MeOD) δ 5.93-pyrazin-2-yl)-1-(3,5- 6.06 (m, 1H), 7.50-7.65 (m, dichlorophenyl)-2,2,2-4H). trifluoroethane-1- sulfonamide 239694 142 3-[(5-bromo-3-hydroxy-428.9 (500 MHz, MeOD) δ 2.65 (t, pyrazin-2-yl)sulfamoyl]-N,N- 3H), 2.83(t, 3H), 4.81 (d, 2H), diethylbenzamide 5.13 (d, 2H), 8.81 (s, 1H),9.17- 9.25 (m, 2H), 9.59-9.63 (m, 1H), 9.70 (m, 1H). 239721 143N-(2-chloro-5-hydroxy- (500 MHz, DMSO) δ 4.90 (s,pyrimidin-4-yl)-1-(3,5- 2H), 7.31-7.38 (m, 2H), 7.64dichlorophenyl)methane- (s, 1H), 7.97 (s, 1H). sulfonamide 239720 1443,4-dichloro-N-(2-chloro-5- 353.7 (500 MHz, DMSO) δ7.99-hydroxypyrimidin-4- 7.82 (m, 3H), 8.23 (d, 1H). yl)benzene-1-sulfonamide239735 145 3,5-dichloro-N-(2-chloro-5- 353.6 (500 MHz, DMSO) δ 7.91 (s,hydroxypyrimidin-4- 1H), 7.97 (s, 3H). yl)benzene-1-sulfonamide 239737146 3-[(6-chloro-4-hydroxy- 384.9 (500 MHz, DMSO) δ 0.99 (s,pyridazin-3-yl)sulfamoyl]- 3H), 1.16 (s, 3H), 6.53 (s, 1H),N,N-diethylbenzamide 7.61-7.71 (m, 2H), 7.91 (s, 1H), 8.01 (m, 1H).239722 147 N-(6-chloro-4-hydroxy- 325.0 (500 MHz, DMSO) δ 4.88 (s,pyridazin-3-yl)-1-(4-cyano- 2H), 6.42 (s, 1H), 7.52 (d, 2H),phenyl)methanesulfonamide 7.83 (d, 2H). 239742 148N-(6-chloro-4-hydroxy- 342.9 (500 MHz, DMSO) δ 4.88 (s,pyridazin-3-yl)-1-(5-cyano-2- 2H), 6.62 (s, 1H), 7.49 (t, 1H),fluorophenyl)methane- 7.90-8.02 (m, 2H). sulfonamide 239743 149N-(6-chloro-4-hydroxy- 342.9 (500 MHz, DMSO) δ 4.87 (s,pyridazin-3-yl)-1-(3-cyano-5- 2H), 6.64 (s, 1H), 7.57 (d, 1H),fluorophenyl)methane- 7.66 (s, 1H), 7.82-7.96 (m, sulfonamide 1H).239744 150 1-(2-chloro-5-cyanophenyl)- 358.9 (250 MHz, DMSO) δ 5.09 (s,N-(2-chloro-5-hydroxy- 2H), 7.73 (d, 1H), 7.88 (dd,pyrimidin-4-yl)methane- 1H), 7.94-8.00 (m, 2H). sulfonamide 239745 1512-chloro-N-(6-chloro-4- 344.9 (250 MHz, DMSO) δ 6.62 (s,hydroxypyridazin-3-yl)-4- 1H), 8.03 (d, 1H), 8.19 (d,cyanobenzene-1-sulfonamide 1H), 8.24 (s, 1H). 239748 1523-chloro-N-(6-chloro-4- 337.8 (250 MHz, DMSO) δ 6.52 (s,hydroxypyridazin-3-yl)-4- 1H), 7.66 (t, 1H), 7.92-8.01fluorobenzene-1-sulfonamide (m, 1H), 8.15 (dd, 1H). 239750 1533,5-dichloro-N-(5-cyano-4- 343.8 (500 MHz, DMSO-d6) δ 7.82hydroxypyridin-3-yl)- (d, 2H), 7.90 (d, 1H), 7.95 (t,benzene-1-sulfonamide 1H), 8.37 (s, 1H). 239754 1543-chloro-N-(6-chloro-4- 337.9 (500 MHz, DMSO) δ 6.58 (s,hydroxypyridazin-3-yl)-5- 1H), 7.73-7.79 (m, 1H), 7.83fluorobenzene-1-sulfonamide (d, 1H), 7.85 (s, 1H). 239755 1553,5-dichloro-N-(4-hydroxy-6- 396.9 (500 MHz, MeOD-d4) δ 3.17methanesulfonylpyridin-3- (s, 3H), 7.37 (s, 1H), 7.72 (d,yl)benzene-1-sulfonamide 1H), 7.75 (d, 2H), 8.53 (s, 1H). 239756 1563,5-dichloro-N-(6-chloro-4- 352.8 (500 MHz, MeOD-d4) δ 6.70hydroxypyridin-3-yl)- (s, 1H), 7.69(d, 2H), 7.70 (d,benzene-1-sulfonamide 1H), 8.12 (s, 1H). 239760 1571-(3,5-dichlorophenyl)-N-[5- 402.0 (250 MHz, DMSO) δ 4.97 (s,hydroxy-2-(trifluoromethyl)- 2H), 7.32 (s, 2H), 7.65 (t, 1H),pyrimidin-4-yl]methane- 8.24 (s, 1H). sulfonamide 239761 1583-chloro-5-fluoro-N-[5- 372.0 (250 MHz, DMSO) δ 7.72-hydroxy-2-(trifluoromethyl)- 7.85 (m, 2H), 7.89 (s, 1H),pyrimidin-4-yl]benzene-1- 8.11 (s, 1H). sulfonamide 239762 1593,5-dichloro-N-(3-hydroxy-5- 397.8 (500 MHz, MeOD-d4) δ 3.14methanesulfonylpyrazin-2- (s, 3H), 7.69-7.87 (m, 2H),yl)benzene-1-sulfonamide 8.04 (d, 2H). 239763 1603-chloro-4-[(6-chloro-4- 418.9 (500 MHz, MeOD) δ 1.15 (t,hydroxypyridazin-3-yl)- 3H), 1.27 (t, 3H), 3.27 (q, 2H),sulfamoyl]-N,N-diethyl- 3.57 (q, 2H), 6.50 (s, 1H), 7.53 benzamide (dd,1H), 7.62 (d, 1H), 8.32 (d, 1H). 239769 161 3-chloro-5-{[(6-chloro-4-433.3 (500 MHz, MeOD) δ 1.09 (t, hydroxypyridazin-3-yl)- 3H),1.23 (t,3H), 3.24 (d, 2H), sulfamoyl]methyl}-N,N- 3.53 (d, 2H), 4.82 (s,diethylbenzamide 2H), 6.55 (s, 1H), 7.29 (t, 1H), 7.38-7.46 (m, 1H),7.51 (t, 1H). 239771 162 N-(6-chloro-4-hydroxy- 328.8 (500 MHz, DMSO) δ6.59 (s, pyridazin-3-yl)-3-cyano-5- 1H), 8.10 (dd, 1H), 8.22 (bs,fluorobenzene-1-sulfonamide 2H). 239772 163 3-chloro-5-fluoro-N-[4-371.9 (500 MHz, DMSO) δ 6.95 (s, hydroxy-6-(trifluoromethyl)- 1H), 7.78(d, 2H), 7.87 (s, 1H). pyridazin-3-yl]benzene-1- sulfonamide 239773 1641-(3,4-dichlorophenyl)-N-[5- 401.8 (250 MHz, DMSO) δ 4.95 (s,hydroxy-2-(trifluoromethyl)- 2H), 7.22 (dd, 1H), 7.54 (d,pyrimidin-4-yl]methane- 1H), 7.64 (d, 1H), 8.21 (s, 1H). sulfonamide239775 165 N-(6-chloro-4-hydroxy- 373.6 (500 MHz, DMSO) δ 4.75 (s,pyridazin-3-yl)-1-(2,5- 2H), 6.60 (s, 1H), 7.08 (s, 1H).dichlorothiophen-3-yl)- methanesulfonamide 239776 1663,5-dichloro-N-(4-hydroxy-6- 398.0 (500 MHz, DMSO) δ 3.17 (s,methanesulfonylpyridazin-3- 3H), 5.74 (s, 1H), 7.71 (m,yl)benzene-1-sulfonamide 1H), 7.82 (d, 2H). 239434 1671-(3,5-dichlorophenyl)-N-(3- (500 MHz, DMSO-d6) δ 4.31hydroxypyridin-4-yl)- (2, 2H), 7.19 (d, 1H), 7.45 (d, methanesulfonamide2H), 7.52 (d, 1H), 7.73 (bd, 1H), 7.77 (bs, 1H), 12.7 (bs, 1H). 239564168 6-(2,5-dichlorothiophene-3- (500 MHz, DMSO-d6 + TFA) δsulfonamido)-5-hydroxy- 7.44 (s,1 H), 7.50 (d,1H), 8.07pyridine-3-carboxylic acid (s, 1H). 239757 169 N-(2-chloro-3-hydroxy-(500 MHz, DMSO-d6) δ 4.73 pyridin-4-yl)-1-(3,5-dichloro- (s, 2H), 7.20(d, 1H), 7.40 (s, phenyl)methanesulfonamide 2H), 7.59 (s, 1H), 7.72 (d,1H), 9.8 (bs, 1H), 10.1 (bs, 1H). 239766 170 3,5-dichloro-N-(2-chloro-3-(500 MHz, DMSO-d6) δ 7.26 hydroxypyridin-4-yl)- (d, 1H), 7.79 (d, 1H),7.93 (d, benzene-1-sulfonamide 2H), 8.00 (t, 1H), 10.3 (bs, 2H). 239447171 N-(3-hydroxypyridin-2-yl)-3- −317 (500 MHz, DMSO) δ 6.82 (bs,(trifluoromethyl)benzene-1- 1H), 7.15 (d, 1H), 7.52 (bs, sulfonamide1H), 7.81 (t, 1H), 8.00 (d, 1H), 8.25 (d, 1H), 8.33 (s, 1H) 239560 172N-(5-chloro-2-hydroxy- −365 (500 MHz, DMSO) δ 4.75 (s,pyridin-3-yl)-1-(3,4-dichloro- 2H), 7.01 (d, 1H), 7.33 (d,phenyl)methanesulfonamide 1H), 7.38 (dd, 1H), 7.61 (d, 1H), 7.63 (d,1H), 9.10 (bs, 1H), 12.25 (bs, 1H) 239562 173 N-(5,6-dichloro-2-hydroxy-−399 (500 MHz, DMSO) δ 4.62 (s, pyridin-3-yl)-1-(3,5-dichloro- 2H), 7.41(d, 2H), 7.56 (m, phenyl)methanesulfonamide 2H), 9.66 (bs, 1H), 12.70(bs, 1H) 239580 174 N-(6-chloro-2-hydroxy- −365 (500 MHz, DMSO) δ 4.60pyridin-3-yl)-1-(3,4-dichloro- (s,2H), 6.80 (bs, 1H), 7.38 (dd,phenyl)methanesulfonamide 1H), 7.47(d, 1H), 7.62 (d, 1H), 7.65 (d, 1H),9.30 (bs, 1H), 12.50 (bs, 1H) 239581 175 N-(6-chloro-2-hydroxy- (500MHz, DMSO) δ 4.60 (s, pyridin-3-yl)-1-(3,5-dichloro- 2H), 6.78 (bs, 1H),7.46 (d, phenyl)methanesulfonamide 2H), 7.48 (d, 1H), 7.59 (t, 1H), 9.30(s, 1H), 12.50 (bs, 1H) 239583 176 5-bromo-N-(6-chloro-2- −392 (500 MHz,DMSO) δ 4.00 (s, hydroxypyridin-3-yl)-6- 3H), 6.86 (bs, 1H), 7.57 (d,methoxypyridine-3- 1H), 8.27 (s, 1H), 8.44 (s, 1H), sulfonamide 10.02(bs, 1H), 12.13 (bs, 1H) 239653 177 N-(5,6-dibromo-3-hydroxy- −488 (500MHz, DMSO) δ 4.84 (s, pyrazin-2-yl)-1-(3,4- 2H), 7.29 (dd, 1H), 7.61 (d,dichlorophenyl)methane- 1H), 7.64 (d, 1H) sulfonamide 239672 178N-(6-chloro-2-hydroxy- (500 MHz, DMSO) δ 4.68 (s,pyridin-3-yl)-1-[4-(trifluoro- 2H), 6.74 (bs, 1H), 7.43 (d,methyl)phenyl]methane- 1H), 7.62 (d, 2H), 7.71 (d, sulfonamide 2H), 9.30(bs, 1H), 12.50 (bs, 1H) 239673 179 N-(6-chloro-2-hydroxy- (500 MHz,DMSO) δ 0.90 (t, pyridin-3-yl)-4-propyl- 3H), 1.61 (m, 2H), 2.65 (t,benzene-1-sulfonamide 2H), 6.82 (bs, 1H), 7.43 (d, 2H), 7.55 (d, 1H),7.72 (d, 2H), 9.69 (bs, 1H), 12.11 (bs, 1H) 239674 1803,4-dichloro-N-(6-chloro-2- (500 MHz, DMSO) δ 6.85 (bs,hydroxypyridin-3-yl)- 1H), 7.56 (d, 1H), 7.66 (dd, benzene-1-sulfonamide1H), 7.84 (d, 1H), 7.96 (d, 1H), 10.15 (bs, 1H), 12.20 (bs, 1H) 239718181 N-(6-chloro-2-hydroxy- (500 MHz, DMSO) δ 4.68 (s,pyridin-3-yl)-1-(5,6-dichloro- 2H), 6.82 (d, 1H), 7.59 (d,pyridin-3-yl)methane- 1H), 8.18 (s, 1H), 8.42 (s, 1H), sulfonamide 9.48(bs, 1H), 12.24 (bs, 1H) 239724 182 N-(6-chloro-2-hydroxy- 364 (500 MHz,DMSO) δ 3.98 (s, pyridin-3-yl)-1-(5-chloro-6- 3H), 4.59 (s, 2H), 6.83(bs, methoxypyridin-3-yl)- 1H), 7.54 (d, 1H), 7.92 (s, 1H),methanesulfonamide 8.15 (s, 1H), 9.35 (bs, 1H), 12.57 (bs, 1H) 239726183 N-(5-chloro-4-hydroxy- (500 MHz, DMSO) δ 4.67 (s,pyridin-3-yl)-1-(5,6- 2H), 7.79 (d, 1H), 8.17 (d, dichloropyridin-3-yl)-1H), 8.35 (d, 1H), 8.49 (d, methanesulfonamide 1H), 9.20 (bs, 1H), 12.10(bs, 1H) 239740 184 N-(5-chloro-4- (500 MHz, DMSO) δ 3.97 (s,hydroxypyridin-3-yl)-1-(5- 3H), 4.57 (s, 2H), 7.74 (d, 1H),chloro-6-methoxypyridin-3- 8.02 (d, 1H), 8.15 (d, 1H), 8.18yl)methanesulfonamide (d, 1H) 239741 185 N-(6-chloro-2-hydroxy- (500MHz, DMSO) δ 1.90 (m, pyridin-3-yl)-1-[5-chloro-6- 4H), 3.60 (t, 4H),4.45 (s, 2H), (pyrrolidin-1-yl)pyridin-3- 6.82 (bs, 1H), 7.49 (bs, 1H),yl]methanesulfonamide 7.62 (d, 1H), 8.00 (d, 1H), 9.21 (bs, 1H), 12.46(bs, 1H) 239758 186 N-(6-chloro-2-hydroxy- 393 (500 MHz, DMSO) δ 1.27(t, pyridin-3-yl)-1-[3-chloro-5- 3H), 3.00 (q, 2H), 4.61 (s, 2H),(ethylsulfanyl)phenyl]- 6.79 (broad signal, 1H), 7.28 methanesulfonamide(d, 2H), 7.34 (s, 1H), 7.48 (d, 1H), 9.30 (bs, 1H), 12.50 (bs, 1H).239768 187 3,5-dichloro-N-[6-(ethane- 411 (500 MHz, DMSO) δ 1.13 (t,sulfonyl)-2-hydroxypyridin- 3H), 3.35 (m, 2H), 7.53 (bs,3-yl]benzene-1-sulfonamide 1H), 7.83 (bs, 1H), 7.92 (bs, 2H), 8.04 (t,1H), 10.54 (bs, 1H), 12.83 (bs, 1H) 239774 1881-(3,5-dichlorophenyl)-N-[6- 425 (500 MHz, DMSO) δ 1.16 (t,(ethanesulfonyl)-2-hydroxy- 3H), 3.35 (m, 2H), 4.75 (s,pyridin-3-yl]methane- 2H), 7.44 (bs, 1H), 7.48 (s, sulfonamide 2H), 7.65(s, 1H), 7.76 (bs, 1H), 9.76 (bs, 1H), 12.88 (bs, 1H) 239401 189N-(5-cyano-3-hydroxy- 357.8 (500 MHz, MeOD) δ 4.89 (s,pyridin-2-yl)-1-(3,5-dichloro- 2H). 7.27-7.38 (m, 3H), 7.45phenyl)methanesulfonamide (t, 1H), 8.18 (s, 1H). 239630 1905-chloro-N-(5-chloro-4- 333.9 (500 MHz, DMSO) δ 2.61 (s,hydroxypyridin-3-yl)-6- 3H), 7.88 (s, 1H), 8.07 (s, 1H),methylpyridine-3- 8.23 (s, 1H), 8.69 (s, 1H). sulfonamide 239631 191N-(5-chloro-4-hydroxy- 340.9 (500 MHz, MeOD) δ 4.13 (s,pyridin-3-yl)-5-cyano-6- 3H), 8.00 (s, 1H), 8.05 (s, 1H),methoxypyridine-3- 8.47 (d, 1H), 8.70 (d, 1H). sulfonamide 239629 192N-(5-chloro-4-hydroxy- 391.9 (500 MHz, DMSO) δ 3.94 (s,pyridin-3-yl)-6-methoxy-5- 3H), 7.41-7.51 (m, 3H), 7.56phenylpyridine-3- (d, 2H), 7.89 (s, 1H), 8.03- sulfonamide 8.11 (m, 2H),8.50 (s, 1H). 239347 193 N-(5-chloro-3-hydroxy- 362.1 (400 MHz, DMSO) δ7.14 (d, pyridin-2-yl)-5-phenyl- 1H), 7.45-7.52 (m, 1H), 7.52-pyridine-3-sulfonamide 7.60 (m, 2H), 7.70 (d, 1H), 7.77 (dd, 2H), 8.55(t, 1H), 9.05 (d, 1H), 9.11 (d, 1H), 10.66 (s, 2H). 239509 194N-(6-chloro-4-hydroxy- 358.9 (500 MHz, MeOD) δ 4.84 (s,pyridazin-3-yl)-1-(3-chloro- 2H), 6.55 (s, 1H), 7.73 (s, 1H),5-cyanophenyl)methane- 7.76 (s, 1H), 7.83 (s, 1H) sulfonamide 1955-bromo-6-chloro-N-(6- 398.7 chloro-4-hydroxypyridazin-3-yl)pyridine-3-sulfonamide 196 N-(5-bromo-4- 250 MHz, DMSO-d6) δ 7.78hydroxypyridin-3-yl)-3,5- (s, 2H), 7.81-7.88 (m, 1H), dichlorobenzene-1-7.93 (s, 1H), 8.06-8.22 (m, sulfonamide 1H)

Biological Assays

Biological Reagents Prepared and Purified for S100A9 Related Assays

Recombinant Human S100A9 Wild Type

Cultivation:

Expression of rhS100A9 wt was performed by shake flask cultivations ofthe working cell bank BL21(DE3)/pET1120 (pLR757) with 0.5 mM IPTGinduction. Cell pellets were frozen.

Purification of Inclusion Bodies:

The E. coli pellets were thawed at RT with 150 mL Lysis buffer (50 mMTris/HCl, 1 mM EDTA, 25% Saccarose, pH 8.0) and sonicated 3×15 s underice in a beaker. Thereafter 10 μL of 1 M MgCl₂ (10 mM end conc.)/mLpellet solution, 1 μL 1 M MnCl₂ (1 mM end conc.)/mL pellet solution and1 μL 10 mg/mL DNase I (10 μg/mL end conc.)/mL pellet solution wereadded. After 30 min of incubation in RT a detergent buffer (20 mMTris/HCl, pH 7.5, 2 mM EDTA, 1% Nonidet P-40) with protease inhibitor(Complete Mini Protease Inhibitors, Roche), 1-2 tablets/25 mL was addedin a 1:1 volume ratio. The solution was centrifuged at 14,000×g, 5° C.,for 20 min. The pellet was resuspended with 90 mL 0.5% Triton X-100, 1mM EDTA for sonication 3×15 s and was spinned down again. This wash andsonication procedure was repeated for additionally 5 times.

Resuspension and Folding:

Milli-Q water was used in all solutions and dialysis steps. The finalpellet was resuspended in 100 mL of 8 M urea, 40 mM DTT in 500 mMNaH₂PO₄ buffer, pH 1.8. When the solution was clear it was centrifugedat 20,000×g, 5° C. for 25 min. The supernatant containing theresuspended inclusion bodies was set to pH 2 with the 500 mM phosphatebuffer, pH 1.8.

First dialysis of the supernatant was against 5 L 50 mM NaH₂PO₄ buffer,1.5 mM DTT, pH 2 for 6 h. Second dialysis against 5 L 10 mM Na-acetatebuffer, 150 mM NaCl, 1.5 mM DTT, pH 4 for 15 h. Third dialysis against 5L 10 mM Na-acetate buffer, 150 mM NaCl, 1.5 mM DTT, pH 4 for 8 h. Fourthdialysis against 5 L 20 mM Tris/HCl, 150 mM NaCl, 1.5 mM DTT, pH 7.2 for16 h. Fifth dialysis against 5 L 20 mM Tris/HCl, 1 mM EDTA, 1 mM EGTA,1.5 mM DTT, pH 8.5 for 6 h. Centrifugation was done at 22,000×g, 5° C.for 30 min.

Purification by Chromatography:

All chromatography columns and resins were purchased from GE HealtCare,Sweden. DTT was added to a final concentration of 1.5 mM. Ananion-exchange chromatography on a HiPrep Q FF 16/10 column was run at aflow-rate of 1.5 mL/min using a 0-1 M NaCl gradient in 20 mM Tris, 1 mMEDTA, 1 mM EGTA, 1.5 mM DTT, pH 8.5 for elution of proteins. The samebuffer, without NaCl, was used for equilibration and washing beforeelution. The pooled fractions containing rhS100A9 wt were concentratedto 1.5 mL using Centriprep YM-3 (Amicon, USA). The size-exclusionchromatography on a Superdex 75 16/790 column was run at a flow-rate of0.5 mL/min using a HBS-N buffer (10 mM Hepes, 150 mM NaCl, pH 7.4)supplemented with 10 mM DTT. A PD-10 was run for buffer exchange to 10mM Hepes, 150 mM NaCl, pH 7.5.

Biacore Binding Assays

The Ca²⁺ and Zn²⁺ dependent interaction of S100A9 with its targetreceptors—e.g. RAGE, TLR4/MD2 and EMMPRIN—was studied using surfaceplasmon resonance (SPR) technology (Björk et al. 2009). Briefly, S100A9was injected over RAGE, TLR4/MD2 or EMMPRIN, immobilized via primaryamines on a Biacore sensor chip, in the presence of physiologicalconcentrations of Ca²⁺ and Zn²⁺ allowing label-free and real-timeanalysis of these interactions. Recombinant human RAGE and EMMPRIN, bothfused with human IgG1Fc, and TLR4/MD2 were all purchased from R&DSystems. Obviously, the assay can be reversed in the way that S100A9 isimmobilized and RAGE, TLR4/MD2 or EMMPRIN is injected. The person ofordinary skill in the art will be able to perform essentially the sameassay directed to the interaction of S100A9 and TLR4/MD2 or EMMPRIN.

The assay showed the inhibitory effect of studied inventive compounds onprotein-protein interactions between S100A9 and RAGE, TLR4/MD2 orEMMPRIN, respectively, cf. FIG. 2.

Inhibition Assay, Biot-hS100A9:hRAGE-Fc

Principle.

The AlphaScreen (Amplified Luminescent Proximity Homogeneous Assay)contains two types of beads, Alpha Donor beads and Acceptor beads(PerkinElmer). Upon laser excitation at 680 nm a photosensitizer in theDonor bead converts ambient oxygen to a more excited singlet state. Thesinglet oxygen molecule diffuses (maximum 200 nm) to react with athioxene derivative in the Acceptor bead and generates achemiluminescence reaction. Fluorophores in the Acceptor beadsubsequently emit light at 520-620 nm which can be detected in theEnVision® Multilabel plate Reader (PerkinElmer). The beads are lightsensitive and all work with the beads is performed under subdued lightconditions or using green filters on light sources (Roscolux ChromaGreen #389, Rosco).

In the AlphaScreen Inhibition Assay described here, protein A(Staphylococcus aureus) conjugated Acceptor beads are used together withstreptavidin coated Donor beads (Perkin Elmer 6760617M). The Acceptorbeads are pre-incubated with Fc-tagged recombinant human RAGE(rhRAGE-Fc) allowing binding of the rhRAGE-Fc to protein A on the beads.Biotinylated human S100A9 (biot-hS100A9) is pre-incubated with the lowmolecular test compounds. The pre-mixes are then added to the wells of amicro-plate and incubated allowing interaction between biot-hS100A9 andrhRAGE-Fc. Subsequent addition of streptavidin coated Donor beads causesbinding of the streptavidin to the biotinylated hS100A9. After anadditional incubation the signal is measured.

Without inhibitory compounds, the interaction of biot-hS100A9 torhRAGE-Fc will bring the Acceptor and Donor beads in close proximitythus generating a high signal. With an inhibitor present the complexwill not form resulting in a decreased signal.

Chemicals and reagents.

-   -   AlphaScreen® General IgG (Protein A) Detection Kit, (PerkinElmer        6760617M)        -   HBS-P buffer (GE Healthcare, BR-1003-68)        -   HBS-N buffer (GE Healthcare, BR-1003-69)        -   CaCl₂ in HBS-P        -   ZnCl₂ in Milli-Q water        -   DMSO    -   Biotinylated hS100A9, (biotinylated via cystein by EZ-link        Iodoacetyl-PEG2-Biotin reagent (Pierce no. 21334), in HBS-N        -   rhRAGE-Fc (R&D Systems, 1145-RG-50), in HBS-P

Procedure.

The AlphaScreen assay method is used for screening of the inhibitoryeffect of different compound samples at fixed concentrations or for IC50determination by varying the compound concentrations. Samples of testcompounds and references are prepared from solutions in DMSO. Relevantreference inhibitors and DMSO are used as controls for definedinhibition and non-inhibition, respectively in the assay. The percentinhibition in assay for test compounds and references are calculated bycomparing their obtained assay signals with the signal values for thecontrol with only DMSO (no compound).

Assay concentration of biotinylated hS100A9 and rhRAGE-Fc are batchdependent, and are determined and defined by separate cross-titrationexperiments using this AlphaScreen inhibition method to verify theoptimal setup regarding signal strength and achievement of a definedinhibition with relevant reference compounds. The Final assayconcentrations of Acceptor and Donor beads are 20 μg/mL.

Experimental Set Up for Screening, Preparation of Solutions and Beads.

Assay buffer is prepared by adding CaCl₂ and ZnCl₂ to HBS-P and is usedfreshly prepared in the experiment.

Biotin-hS100A9 solution for the experiment is prepared by dilution ofappropriate amount of stock solution biot-hS100A9 in assay buffer (withCaCl₂ and ZnCl₂) and incubation in room temperature for 30 minutes.

rhRAGE-Fc solution for the experiment is prepared by dilutionappropriate amount of rhRAGE-Fc stock in assay buffer.

Protein A Acceptor beads are diluted in assay buffer and are added to anequal volume of the prepared diluted rhRAGE-Fc solution. The beads arelight sensitive. The vial is covered with aluminum foil and incubated atroom temperature in the dark until biot-hS100A9+ compound incubation isfinished (see below).

Streptavidin-coated Donor beads are diluted in assay buffer. The beadsare very light sensitive. The vial is covered with aluminum foil andincubated at room temperature in the dark until use (see below).

Dilution of Samples and Incubation with Biot-hS100A9

Samples of test compounds, appropriate references and DMSO control arediluted in assay buffer.

The diluted test compounds, references and DMSO control are added towells on a Greiner micro titer 96 well plate (PP, u-bottom (no. 650201))and appropriate amount of diluted biot-hS100A9 solution are added toeach well with samples (final DMSO conc. <1.25% (v/v)). The plate iscovered with a plate seal and is incubated in the dark on an orbitalplate shaker for 1 h at room temperature.

Incubation of Biot-hS100A9+Compound Samples and rhRAGE-Fc-Acceptor Beadsin Optiplate

When the biot-hS100A9+ compound incubation is finished the solutions aretransferred to Optiplate (Optiplate 384 white, Perkin Elmer no. 6007299)and rhRAGE-Fc-Acceptor bead solution is added to each well (use greenfiltered light). The plate is covered with a plate seal and incubated inthe dark in a plate incubator at 25° C. nominally for 40 minutes.

Incubation of Biot-hS100A9+Compound Samples and rhRAGE-Fc-Acceptor andDonor Beads in Optiplate

After incubation Donor bead solution is added to each well (use greenfiltered light). The plate is covered with a plate seal and incubated inthe dark in a plate incubator at 25° C. nominally. After 50 minutes, theplate is incubated (in the dark) on the bench next to the EnVision®instrument for 10 minutes, for temperature equilibrium.

Reading of Optiplate in EnVision® Multilabel Plate Reader

The plate seal is removed and the plate is placed in the EnVision® for 5minutes before reading.

Calculations

Percent (%) inhibition for each sample (test compound or reference) iscalculated using the formula: 1−(Signal sample/Signal DMSO)×100%.

The IC50 values for a number of compounds of the invention in theS100A9-RAGE inhibition assay are listed in Table 2.

TABLE 2 Ex. No. ABR ref IC50 μM 9 239247 0.12 11 239249 >1 13 239269 3.120 239315 <1 32 239338 0.14 36 239372 0.1 40 239183 3.0 41 239239 >1 59238901 2.80 62 238868 4.4 63 238581 4.6 70 239286 0.80 73 239167 1.2 74239129 2.6 75 239417 0.25 76 239462 <1 85 239571 0.98 88 239676 >1 89239610 2.10 94 239532 0.30 95 239477 0.7 96 239485 0.41 97 239565 3.8102 239607 2.2 103 239613 <1 107 239553 4.00 111 239524 0.1 112 2396190.42 113 239491 2.0 114 239502 1.0 122 239554 >1 127 239465 1.11 130239641 0.39 131 239466 0.12 134 239671 0.53 136 239481 >1 137 239575 1.8138 239566 3.9 139 239531 <1 141 239717 <1 143 239721 0.18 144 239720 <1155 239755 >1 157 239760 <1 159 239762 1.8 161 239769 5.1 163 239772 >1167 239434 <1 170 239766 <1 172 239560 3.1 173 239562 <1 178 239672 >1179 239673 <1 182 239724 <1 185 239741 <1 186 239758 <1 188 239774 <1189 239401 0.12

In Vivo Model MC38/Mouse.

Female C57Bl/6 mice about seven weeks old were purchased. Before theonset of the studies the mice were acclimatized at the laboratory for atleast one week. The mice were routinely used at the aged of 8 to 12weeks. In all experiments a control group of mice was randomly selected.The control group was handled exactly as the treated group but notadministrated with any drug compound. Provoking the tumor disease wasmade by subcutaneous injections with 100 000 or 500 000 MC38-C215 cellsin 100 μl matrigel (day 0). This cell line was C215-transfected murineMC38 colon adenocarcinoma cells which were cultured in R₁₀ medium(RPMI-1640 with Ultraglutamine supplemented with 10% fetal bovine serum,50 μM β-mercaptoethanol and 0.5 mg/ml G418 Sulfate). From day 7 thetumor growth was measured three times a week with a caliper and tumorvolume was calculated. The tumor volume was calculated as V=L×W²×0.4,where V is the volume (mm²), L is the length (mm) and W is the width(mm) and L> or =W (Attia 1966). When tumors in the control group hadreached a suitable size the experiment was completed and all the micewere sacrificed (usually on day 12-16) and the tumors were dissected outand the tumor mass was determined. Results are shown in FIG. 3.

Prodrug Assay

ABR-239313, 239470 and 239749 were administered to seven C57 Bl/6 miceas a cassette formulation either intravenously (4 animals, nominal 1mg/kg) or per oral (3 animals, nominal 5 mg/kg).

Blood samples were collected at time points ranging from 5 minutes to 7hours after administration. After sample withdrawal, plasma was directlyseparated and frozen until analysis.

The plasma as well as the formulation samples were analyzed with respectto the concentration of ABR-239313, 239470, 239749 and the correspondingdemethylated compounds, i.e. Examples 9, 75 and 73 (ABR-239247, 239417and 239167) by means of LC-MS.

The samples were precipitated with acidified acetonitrile andcentrifuged prior to injection on LC-MS system (consisting of a triplequadrupole instrument operated in negative MRM ionization mode, and afast-gradient reversed-phase LC on a Symmetry Shield RP18, 2×30 mm, 3.5um column).

In Table 3 the concentrations of each analyte are presented.

TABLE 3 Prodrug Parent Prodrug Parent Prodrug Parent Formulation 239313239247 239470 239417 239749 239167 Time Conc. Conc. Conc. Conc. Conc.Conc. Route (h) (μM) (μM) (μM) (μM) (μM) (μM) — Predose 0 <LLOQ <LLOQ<LLOQ <LLOQ <LLOQ <LLOQ i.v. Solution 0.083 6.3 0.044 25.2 0.12 32.20.089 i.v. Solution 0.5 0.55 0.005 16.8 0.32 19.3 0.20 i.v. Solution 10.084 0.003 17.5 0.32 23.7 0.19 i.v. Solution 2 0.38 0.006 14.9 0.3217.5 0.21 i.v. Solution 4 0.17 0.004 9.2 0.21 7.8 0.18 i.v. Solution 70.15 0.004 6.2 0.20 2.5 0.13 p.o. Solution 0.5 3.6 0.045 51.7 0.57 86.80.46 p.o. Solution 1 1.6 0.026 69.4 0.86 91.6 0.49 p.o. Solution 2 1.30.021 78.9 0.80 109.2 0.69 p.o. Solution 4 0.85 0.012 59.4 0.63 47.10.61 p.o. Solution 7 0.70 0.019 73.5 1.10 50.3 0.78 Formulation solution41% <0.1%  99% <0.8% 108% <0.7% 0.1 mg/ml Formulation solution 1 mg/ml82% <0.1% 113% <0.8% 118% <0.7% LLOQ = 0.05, 0.002, 0.02, 0.01, 0.02 and0.01 μM for 239313, 239247, 239470, 239417, 239749 and 239167,respectively.

Abbreviations Used

AcOH acetic acidCHRM cryopreserved hepatocyte recovery mediumDCM dichloromethaneDMF N,N-dimethyl formamideDMSO dimethyl sulfoxideDTT dithiothreitolEDTA ethylenediaminetetraacetic acidEGTA ethylene glycol tetraacetic acidEtOAc ethyl acetateEtOH ethanolFAC S fluorescence-activated cell sortingHPLC high performance liquid chromatographyhrs hoursIPTG isopropyl 3-D-1-thiogalactopyranosideKHB Krebs-Henseleit bicarbonate buffermin minutesNMR nuclear magnetic resonancePBS phosphate buffered salinePBST phosphate buffered saline Tween-20RT room temperatureSFC supercritical fluid chromatographyTHF tetrahydrofuranTLC thin layer chromatography

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1. A method of treatment of a disorder selected from the groupconsisting of cancer, an inflammatory disorder, an autoimmunity disorderand a neurodegenerative disorder, by administering, to a mammal in needof such treatment, a compound of formula (I)

or a pharmaceutically acceptable salt thereof; wherein W is N or CH; Xis N or CR₁; Y is N or CR₂; Z is N or CR₃; at least one and at most twoof W, X, Y and Z are N; R₁ is H, halogen, S(O)₂C1-C3 alkyl, cyano, orC1-C3 alkyl optionally substituted with one or more halogen(s); R₂ is H,halogen, cyano, C(O)OH, C(O)OC1-C3 alkyl, C1-C3 alkyl optionallysubstituted with one or more F; hydroxy-C1-C3 alkyl, S(O)₂C1-C3 alkyl,S(O)₂C3-C6 cycloalkyl or S(O)₂C1-C3 hydroxyalkyl; R₃ is H, halogen orcyano; V is (CHR₄)_(m); m is 0 or 1; R₄ is H or C1-C3 alkyl optionallysubstituted with one or more halogen(s); Ar is

R₅ is H, halogen or cyano; R₆ is H or halogen; R₇ is H, halogen, C1-C3alkyl, cyano, S(O)₂C1-C3 alkyl, or phenyl; R₈ is H, halogen, C1-C3 alkyloptionally substituted with one or more F; C1-C3 alkoxy optionallysubstituted with one or more F; phenoxy, NHR₁₁, or NR₁₁R₁₂; R₉ is H,halogen, cyano, C1-C3 alkyl optionally substituted with one or more F;C1-C3 alkylthio optionally substituted with one or more F; C1-C3 alkoxyoptionally substituted with one or more F; or C(O)NR₁₃R₁₄; R₁₀ is H,halogen, cyano, C1-C3 alkyl optionally substituted with one or more F;C1-C3 alkylthio optionally substituted with one or more F; C1-C3 alkoxyoptionally substituted with one or more F; or C(O)NR₁₃R₁₄; R₁₁ is C1-C3alkyl; R₁₂ is C1-C3 alkyl; or R₁₁ and R₁₂, together with the nitrogenatom to which they are both attached, form a ring of formula

R₁₃ is H or C1-C3 alkyl; and R₁₄ is H or C1-C3 alkyl; provided that thecompound is not selected from3,4-difluoro-N-(2-hydroxypyridin-3-yl)benzene-1-sulfonamide,N-[5-bromo-3-hydroxypyridin-2-yl]-4-methylbenzenesulfonamide,N-(1,2-dihydro-2-oxo-3-pyridinyl)-2-(trifluoromethyl)-benzenesulfonamide,4-chloro-N-(1,2-dihydro-2-oxo-3-pyridinyl)-3-(trifluoromethyl)-benzenesulfonamide,4-chloro-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide,3-trifluoromethyl-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide,4-methyl-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide,4-methyl-N-(2-hydroxy-3-pyridinyl)-benzenesulfonamide, and4-methyl-N-(2,3-dihydro-3-oxo-4-pyridazinyl)-benzenesulfonamide or itstautomer 4-methyl-N-(3-hydroxy-4-pyridazinyl)-benzenesulfonamide.
 2. Themethod of claim 1, wherein Ar is


3. The method of claim 1, wherein Ar is


4. The method of claim 1, wherein Ar is


5. The method of claim 1, wherein one of R₉ and R₁₀ is halogen and theother one is selected from H, halogen, cyano, C1-C3 alkyl optionallysubstituted with one or more F; C1-C3 alkylthio optionally substitutedwith one or more F; C1-C3 alkoxy optionally substituted with one or moreF; and C(O)NR₁₃R₁₄.
 6. The method of claim 1, wherein R₉ is H or halogenand R₁₀ is halogen or cyano.
 7. The method of claim 1, wherein R₇ is Hor halogen, and R₈ is H, C1-C3 alkyl optionally substituted with one ormore F; or C1-C3 alkoxy optionally substituted with one or more F. 8.The method of claim 1, wherein R₅ and R₆ are halogens.
 9. The method ofclaim 1, wherein Y is CR₂.
 10. The method of claim 1, wherein W is N.11. The method of claim 1, wherein X is N.
 12. The method of claim 1,wherein Y is CH, Z is CR₃, and R₃ is halogen.
 13. The method of claim 1,wherein Y is CR₂, Z is CH, and R₂ is halogen or S(O)₂C1-C3 alkyl. 14.The method of claim 1, wherein m is 1 and R₄ is H.
 15. The method ofclaim 1, wherein m is
 0. 16. The method of claim 1, wherein the compoundis selected from5-bromo-6-chloro-N-(5-chloro-2-hydroxypyridin-3-yl)pyridine-3-sulfonamide;N-(4-hydroxypyridin-3-yl)benzenesulfonamide;N-(4-hydroxypyridin-3-yl)-4-(trifluoromethyl)benzene-1-sulfonamide;N-(4-hydroxypyridin-3-yl)-4-(trifluoromethoxy)benzene-1-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-phenylmethanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyridine-3-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide;6-chloro-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-6-[(propan-2-yl)amino]pyridine-3-sulfonamide;5-bromo-6-chloro-N-[3-hydroxy-5-(propan-2-yl)pyridin-2-yl]pyridine-3-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3-cyanophenyl)methanesulfonamide;(+)-5-bromo-6-chloro-N-[3-hydroxy-5-(1-hydroxypropan-2-yl)pyridin-2-yl]pyridine-3-sulfonamide;(−)-5-bromo-6-chloro-N-[3-hydroxy-5-(1-hydroxypropan-2-yl)pyridin-2-yl]pyridine-3-sulfonamide;5-bromo-6-chloro-N-(3-hydroxypyridin-2-yl)pyridine-3-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2,4-dichlorophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(4-cyanophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-pyridin-3-ylmethanesulfonamide;5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyridine-3-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-difluorophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2,5-dichlorothiophen-3-yl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,4-dichlorophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3-chloro-5-fluorophenyl)methanesulfonamide;1-(2,4-dichlorophenyl)-N-(4-hydroxypyridin-3-yl)methanesulfonamide;1-(3,5-dichlorophenyl)-N-(4-hydroxypyridin-3-yl)methanesulfonamide;3,5-dichloro-N-(5-chloro-3-hydroxypyridin-2-yl)benzene-1-sulfonamide;3,4-dichloro-N-(5-chloro-3-hydroxypyridin-2-yl)benzene-1-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3-chlorophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(4-chlorophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2-chlorophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2,5-dichlorophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,4-difluorophenyl)methanesulfonamide;1-(3,5-dichlorophenyl)-N-(3-hydroxy-5-methanesulfonylpyridin-2-yl)methane-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3-chloro-5-cyanophenyl)methanesulfonamide;3-chloro-5-{[(5-chloro-3-hydroxypyridin-2-yl)sulfamoyl]methyl}benzamide;1-(5-chloro-2-fluorophenyl)-N-(5-chloro-3-hydroxypyridin-2-yl)methanesulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2,3-dichlorophenyl)methanesulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(2,6-dichlorophenyl)methanesulfonamide;(1R)—N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)ethane-1-sulfonamide;(1S)—N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)ethane-1-sulfonamide;5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)pyridine-3-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide;N-(5-bromo-3-hydroxypyridin-2-yl)benzene sulfonamide;N-(5-bromo-3-hydroxypyridin-2-yl)-2,5-dichlorothiophene-3-sulfonamide;N-(5-bromo-3-hydroxypyridin-2-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide;5-bromo-N-(5-bromo-3-hydroxypyridin-2-yl)-6-chloropyridine-3-sulfonamide;N-(5-bromo-3-hydroxypyridin-2-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide;5-bromo-N-(5-bromo-3-hydroxypyridin-2-yl)-6-methoxypyridine-3-sulfonamide;N-(3-hydroxypyridin-2-yl)-6-(trifluoromethyl)pyri dine-3-sulfonamidemethyl6-(2,5-dichlorothiophene-3-sulfonamido)-5-hydroxypyridine-3-carboxylate;methyl 6-benzenesulfonamido-5-hydroxypyridine-3-carboxylate;4-bromo-3-fluoro-N-(4-hydroxypyridin-3-yl)benzene-1-sulfonamide;N-(5-chloro-2-hydroxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide;5-bromo-N-(5-chloro-2-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide;2,5-dichloro-N-(5-chloro-3-hydroxypyridin-2-yl)thiophene-3-sulfonamide;N-(5-chloro-4-hydroxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide;5-bromo-6-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamide;5-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide;5-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamide;5-bromo-6-chloro-N-(4-hydroxypyridin-3-yl)pyridine-3-sulfonamide;5-bromo-N-(4-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide;2,5-dichloro-N-(4-hydroxypyridin-3-yl)thiophene-3-sulfonamide;N-(4-hydroxypyridin-3-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide;3,4-difluoro-N-(4-hydroxypyridin-3-yl)benzene-1-sulfonamide;3,4-dichloro-N-(4-hydroxypyridin-3-yl)benzene-1-sulfonamide;N-(2-hydroxypyridin-3-yl)-6-(trifluoromethyl)pyri dine-3-sulfonamide;5-bromo-6-chloro-N-(2-hydroxypyridin-3-yl)pyridine-3-sulfonamide;2,5-dichloro-N-(2-hydroxypyridin-3-yl)thiophene-3-sulfonamide;N-(6-chloro-4-hydroxypyridin-3-yl)-1-(3,4-dichlorophenyl)methanesulfonamide;5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)-6-methoxypyridine-3-sulfonamide;3,4-dichloro-N-(3-hydroxypyridin-4-yl)benzene-1-sulfonamide;2,5-dichloro-N-(6-chloro-4-hydroxypyridin-3-yl)thiophene-3-sulfonamide;2,5-dichloro-N-(5-chloro-2-hydroxypyridin-3-yl)thiophene-3-sulfonamide;N-(5-bromo-3-hydroxypyrazin-2-yl)-1-(3,4-dichlorophenyl)methanesulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-difluorophenyl)methanesulfonamide;1-(3,5-dichlorophenyl)-N-[3-hydroxy-5-(propane-2-sulfonyl)pyridin-2-yl]methane-sulfonamide;N-(5-chloro-3-hydroxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;5-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-phenoxypyridine-3-sulfonamide;N-(5-bromo-3-hydroxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2,4-dichlorophenyl)methanesulfonamide;1-(3,5-dichlorophenyl)-N-(4-hydroxy-6-iodopyridazin-3-yl)methanesulfonamide;N-(6-bromo-4-hydroxypyridazin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;3-bromo-N-(5-bromo-4-hydroxypyridin-3-yl)-4-methoxybenzene-1-sulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chloro-5-cyanophenyl)methane-sulfonamide;N-(5-chloro-4-hydroxypyridin-3-yl)-6-phenoxypyridine-3-sulfonamide;N-(6-chloro-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;1-(3-chlorophenyl)-N-[5-(ethanesulfonyl)-3-hydroxypyrazin-2-yl]methane-sulfonamide;3,5-dichloro-N-(5-chloro-4-hydroxypyridin-3-yl)benzene-1-sulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2-chlorophenyl)methanesulfonamide;5-bromo-N-(5-bromo-4-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide;N-(6-bromo-5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)methane-sulfonamide;1-(2-chlorophenyl)-N-(4-hydroxy-6-methanesulfonylpyridazin-3-yl)methane-sulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3-chloro-5-fluorophenyl)methane-sulfonamide;3,5-dichloro-N-(6-chloro-4-hydroxypyridazin-3-yl)benzene-1-sulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3-chlorophenyl)methanesulfonamide;N-(5-bromo-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;3-[(5-chloro-4-hydroxypyridin-3-yl)sulfamoyl]-N,N-diethylbenzamide;1-(3,4-difluorophenyl)-N-(4-hydroxy-6-methanesulfonylpyridazin-3-yl)methane-sulfonamide;3-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)-4-methylbenzene-1-sulfonamide;5-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-(propan-2-yloxy)pyridine-3-sulfonamide;3-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)-4-(trifluoromethoxy)benzene-1-sulfonamide;N-(5-cyano-3-hydroxypyrazin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;1-(3,5-dichlorophenyl)-N-[4-hydroxy-6-(propane-1-sulfonyl)pyridazin-3-yl]methane-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(3,5-dimethoxyphenyl)methanesulfonamide;5-chloro-N-(5-chloro-3-hydroxypyridin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide;N-(2-chloro-4-hydroxypyrimidin-5-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;1-(3,5-dichlorophenyl)-N-[5-(ethanesulfonyl)-3-hydroxypyridin-2-yl]methane-sulfonamide;3,4-dichloro-N-(6-chloro-4-hydroxypyridazin-3-yl)benzene-1-sulfonamide;N-(5-chloro-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;1-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-4-hydroxypyridazin-3-yl]methane-sulfonamide;1-(3,5-dichlorophenyl)-N-(3-hydroxy-5-methanesulfonylpyrazin-2-yl)methane-sulfonamide;2,5-dichloro-N-(6-chloro-4-hydroxypyridazin-3-yl)thiophene-3-sulfonamide;5-bromo-N-(6-chloro-4-hydroxypyridazin-3-yl)-6-methoxypyridine-3-sulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2,3-dichlorophenyl)methanesulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-3-(trifluoromethoxy)benzene-1-sulfonamide;6-(azetidin-1-yl)-5-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)pyridine-3-sulfonamide;1-(3,5-dichlorophenyl)-N-[4-hydroxy-6-(propane-2-sulfonyl)pyridazin-3-yl]methane-sulfonamide;5-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-ethoxypyridine-3-sulfonamide;5-bromo-N-(5-chloro-3-hydroxypyridin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-3-cyanobenzene-1-sulfonamide;3-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)-4-methoxybenzene-1-sulfonamide;3-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-4-methoxybenzene-1-sulfonamide;1-(3,5-dichlorophenyl)-N-[3-hydroxy-5-(propane-1-sulfonyl)pyridin-2-yl]methane-sulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3,4-dichlorophenyl)methanesulfonamide;1-(3,5-dichlorophenyl)-N-(4-hydroxy-6-methanesulfonylpyridazin-3-yl)methane-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-1-(5-cyanothiophen-3-yl)methanesulfonamide;5-bromo-6-chloro-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]pyridine-3-sulfonamide;5-bromo-N-(5-chloro-4-hydroxypyridin-3-yl)-6-(piperidin-1-yl)pyridine-3-sulfonamide;N-(5-chloro-6-cyano-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)methane-sulfonamide;N-[5-(cyclopentanesulfonyl)-3-hydroxypyridin-2-yl]-1-(3,5-dichlorophenyl)methane-sulfonamide;N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-6-methylpyridine-3-sulfonamide;1-(3,5-dichlorophenyl)-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]methane-sulfonamide;N-(5-chloro-3-hydroxy-6-methanesulfonylpyridin-2-yl)-1-(3,5-dichlorophenyl)-methanesulfonamide;1-(3,4-dichlorophenyl)-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]methane-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-6-(dimethylamino)-5-methanesulfonylpyridine-3-sulfonamide;5-bromo-N-[4-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-6-methoxypyridine-3-sulfonamide;N-(5-cyano-4-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;1-(3,5-dichlorophenyl)-N-[4-hydroxy-6-(3-hydroxypropanesulfonyl)pyridazin-3-yl]methanesulfonamide;N-[6-(cyclopentanesulfonyl)-4-hydroxypyridazin-3-yl]-1-(3,5-dichlorophenyl)methane-sulfonamide;(+/−)-N-(5-bromo-3-hydroxypyrazin-2-yl)-1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethane-1-sulfonamide;3-[(5-bromo-3-hydroxypyrazin-2-yl)sulfamoyl]-N,N-diethylbenzamide;N-(2-chloro-5-hydroxypyrimidin-4-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;3,4-dichloro-N-(2-chloro-5-hydroxypyrimidin-4-yl)benzene-1-sulfonamide;3,5-dichloro-N-(2-chloro-5-hydroxypyrimidin-4-yl)benzene-1-sulfonamide;3-[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]-N,N-diethylbenzamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(4-cyanophenyl)methanesulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(5-cyano-2-fluorophenyl)methane-sulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3-cyano-5-fluorophenyl)methane-sulfonamide;1-(2-chloro-5-cyanophenyl)-N-(2-chloro-5-hydroxypyrimidin-4-yl)methane-sulfonamide;2-chloro-N-(6-chloro-4-hydroxypyridazin-3-yl)-4-cyanobenzene-1-sulfonamide;3-chloro-N-(6-chloro-4-hydroxypyridazin-3-yl)-4-fluorobenzene-1-sulfonamide;3,5-dichloro-N-(5-cyano-4-hydroxypyridin-3-yl)benzene-1-sulfonamide;3-chloro-N-(6-chloro-4-hydroxypyridazin-3-yl)-5-fluorobenzene-1-sulfonamide;3,5-dichloro-N-(4-hydroxy-6-methanesulfonylpyridin-3-yl)benzene-1-sulfonamide;3,5-dichloro-N-(6-chloro-4-hydroxypyridin-3-yl)benzene-1-sulfonamide;1-(3,5-dichlorophenyl)-N-[5-hydroxy-2-(trifluoromethyl)pyrimidin-4-yl]methane-sulfonamide;3-chloro-5-fluoro-N-[5-hydroxy-2-(trifluoromethyl)pyrimidin-4-yl]benzene-1-sulfonamide;3,5-dichloro-N-(3-hydroxy-5-methanesulfonylpyrazin-2-yl)benzene-1-sulfonamide;3-chloro-4-[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]-N,N-diethylbenzamide;3-chloro-5-{[(6-chloro-4-hydroxypyridazin-3-yl)sulfamoyl]methyl}-N,N-diethyl-benzamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-3-cyano-5-fluorobenzene-1-sulfonamide;3-chloro-5-fluoro-N-[4-hydroxy-6-(trifluoromethyl)pyridazin-3-yl]benzene-1-sulfonamide;1-(3,4-dichlorophenyl)-N-[5-hydroxy-2-(trifluoromethyl)pyrimidin-4-yl]methane-sulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(2,5-dichlorothiophen-3-yl)methane-sulfonamide;3,5-dichloro-N-(4-hydroxy-6-methanesulfonylpyridazin-3-yl)benzene-1-sulfonamide;1-(3,5-dichlorophenyl)-N-(3-hydroxypyridin-4-yl)methanesulfonamide;6-(2,5-dichlorothiophene-3-sulfonamido)-5-hydroxypyridine-3-carboxylicacid;N-(2-chloro-3-hydroxypyridin-4-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;3,5-dichloro-N-(2-chloro-3-hydroxypyridin-4-yl)benzene-1-sulfonamide;N-(3-hydroxypyridin-2-yl)-3-(trifluoromethyl)benzene-1-sulfonamide;N-(5-chloro-2-hydroxypyridin-3-yl)-1-(3,4-dichlorophenyl)methanesulfonamide;N-(5,6-dichloro-2-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;N-(6-chloro-2-hydroxypyridin-3-yl)-1-(3,4-dichlorophenyl)methanesulfonamide;N-(6-chloro-2-hydroxypyridin-3-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;5-bromo-N-(6-chloro-2-hydroxypyridin-3-yl)-6-methoxypyridine-3-sulfonamide;N-(5,6-dibromo-3-hydroxypyrazin-2-yl)-1-(3,4-dichlorophenyl)methanesulfonamide;N-(6-chloro-2-hydroxypyridin-3-yl)-1-[4-(trifluoromethyl)phenyl]methane-sulfonamide;N-(6-chloro-2-hydroxypyridin-3-yl)-4-propylbenzene-1-sulfonamide;3,4-dichloro-N-(6-chloro-2-hydroxypyridin-3-yl)benzene-1-sulfonamide;N-(6-chloro-2-hydroxypyridin-3-yl)-1-(5,6-dichloropyridin-3-yl)methane-sulfonamide;N-(6-chloro-2-hydroxypyridin-3-yl)-1-(5-chloro-6-methoxypyridin-3-yl)methane-sulfonamide;N-(5-chloro-4-hydroxypyridin-3-yl)-1-(5,6-dichloropyridin-3-yl)methane-sulfonamide;N-(5-chloro-4-hydroxypyridin-3-yl)-1-(5-chloro-6-methoxypyridin-3-yl)methane-sulfonamide;N-(6-chloro-2-hydroxypyridin-3-yl)-1-[5-chloro-6-(pyrrolidin-1-yl)pyridin-3-yl]-methanesulfonamide;N-(6-chloro-2-hydroxypyridin-3-yl)-1-[3-chloro-5-(ethylsulfanyl)phenyl]methane-sulfonamide;3,5-dichloro-N-[6-(ethanesulfonyl)-2-hydroxypyridin-3-yl]benzene-1-sulfonamide;1-(3,5-dichlorophenyl)-N-[6-(ethanesulfonyl)-2-hydroxypyridin-3-yl]methane-sulfonamide;N-(5-cyano-3-hydroxypyridin-2-yl)-1-(3,5-dichlorophenyl)methanesulfonamide;5-chloro-N-(5-chloro-4-hydroxypyridin-3-yl)-6-methylpyridine-3-sulfonamide;N-(5-chloro-4-hydroxypyridin-3-yl)-5-cyano-6-methoxypyridine-3-sulfonamide;N-(5-chloro-4-hydroxypyridin-3-yl)-6-methoxy-5-phenylpyridine-3-sulfonamide;N-(5-chloro-3-hydroxypyridin-2-yl)-5-phenylpyridine-3-sulfonamide;N-(6-chloro-4-hydroxypyridazin-3-yl)-1-(3-chloro-5-cyanophenyl)methane-sulfonamide;5-bromo-6-chloro-N-(6-chloro-4-hydroxypyridazin-3-yl)pyridine-3-sulfonamide;and N-(5-bromo-4-hydroxypyridin-3-yl)-3,5-dichlorobenzene-1-sulfonamide;or a pharmaceutically acceptable salt thereof.
 17. The method of claim1, wherein the disorder is a cancer.
 18. The method of claim 1, whereinthe disorder is colon cancer.
 19. The method of claim 1, wherein thedisorder is associated with activity of S100A9.
 20. A method ofinhibiting interaction between S100A9 and its interaction partners in amammal, by administering to said mammal a compound of formula (I)

or a pharmaceutically acceptable salt thereof; wherein W is N or CH; Xis N or CR₁; Y is N or CR₂; Z is N or CR₃; at least one and at most twoof W, X, Y and Z are N; R₁ is H, halogen, S(O)₂C1-C3 alkyl, cyano, orC1-C3 alkyl optionally substituted with one or more halogen(s); R₂ is H,halogen, cyano, C(O)OH, C(O)OC1-C3 alkyl, C1-C3 alkyl optionallysubstituted with one or more F; hydroxy-C1-C3 alkyl, S(O)₂C1-C3 alkyl,S(O)₂C3-C6 cycloalkyl or S(O)₂C1-C3 hydroxyalkyl; R₃ is H, halogen orcyano; V is (CHR₄)_(m); m is 0 or 1; R₄ is H or C1-C3 alkyl optionallysubstituted with one or more halogen(s); Ar is

R₅ is H, halogen or cyano; R₆ is H or halogen; R₇ is H, halogen, C1-C3alkyl, cyano, S(O)₂C1-C3 alkyl, or phenyl; R₈ is H, halogen, C1-C3 alkyloptionally substituted with one or more F; C1-C3 alkoxy optionallysubstituted with one or more F; phenoxy, NHR₁₁, or NR₁₁R₁₂; R₉ is H,halogen, cyano, C1-C3 alkyl optionally substituted with one or more F;C1-C3 alkylthio optionally substituted with one or more F; C1-C3 alkoxyoptionally substituted with one or more F; or C(O)NR₁₃R₁₄; R₁₀ is H,halogen, cyano, C1-C3 alkyl optionally substituted with one or more F;C1-C3 alkylthio optionally substituted with one or more F; C1-C3 alkoxyoptionally substituted with one or more F; or C(O)NR₁₃R₁₄; R₁₁ is C1-C3alkyl; R₁₂ is C1-C3 alkyl; or R₁₁ and R₁₂, together with the nitrogenatom to which they are both attached, form a ring of formula

R₁₃ is H or C1-C3 alkyl; and R₁₄ is H or C1-C3 alkyl; provided that thecompound is not selected from3,4-difluoro-N-(2-hydroxypyridin-3-yl)benzene-1-sulfonamide,N-[5-bromo-3-hydroxypyridin-2-yl]-4-methylbenzenesulfonamide,N-(1,2-dihydro-2-oxo-3-pyridinyl)-2-(trifluoromethyl)-benzenesulfonamide,4-chloro-N-(1,2-dihydro-2-oxo-3-pyridinyl)-3-(trifluoromethyl)-benzenesulfonamide,4-chloro-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide,3-trifluoromethyl-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide,4-methyl-N-(3-hydroxy-2-pyridinyl)-benzenesulfonamide,4-methyl-N-(2-hydroxy-3-pyridinyl)-benzenesulfonamide, and4-methyl-N-(2,3-dihydro-3-oxo-4-pyridazinyl)-benzenesulfonamide or itstautomer 4-methyl-N-(3-hydroxy-4-pyridazinyl)-benzenesulfonamide. 21.The method of claim 20, wherein the interaction partners are selectedfrom the group consisting of RAGE, TLR4 and EMMPRIN.
 22. The method ofclaim 20, wherein the inhibition of said interaction is used to treat adisorder or condition selected from the group consisting of cancer, aninflammatory disorder, an autoimmunity disorder and a neurodegenerativedisorder.
 23. The method of claim 22, wherein the disorder is cancer.